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Logo of moiMediators of Inflammation
Mediators Inflamm. 2010; 2010: 672395.
Published online 2010 July 13. doi:  10.1155/2010/672395
PMCID: PMC2913853

DAMPening Inflammation by Modulating TLR Signalling


Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

1. The Danger Hypothesis

Both infection and sterile tissue injury generate strong immune responses. This paradox was first resolved by Matzinger in 1994 who proposed that our immune system is designed to combat danger, rather than mediate recognition of non-self over self [1]. Pathogen-associated molecular patterns (PAMPs) and endogenous molecules created upon tissue injury, since called damage-associated molecular patterns (DAMPs), signal the threat of either infection or injury to the organism, independently of their non-self- or self-identity [25]. Among the cellular receptors that sense these danger signals, Toll-like receptors (TLRs) represent a key molecular link between tissue injury, infection, and inflammation. In the last decade a number of endogenous molecules specifically generated upon tissue injury that activate TLRs have been identified. Some are intracellular molecules normally inaccessible to the immune system that are released into the extracellular milieu as a result of cell necrosis or activation following injury. Others are extracellular matrix (ECM) molecule fragments that are released upon tissue damage or ECM molecules that are specifically upregulated in response to tissue injury [6].

In addition to playing a key role in host defence against danger, activation of TLRs has been linked to the pathogenesis of many inflammatory and autoimmune diseases including sepsis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), type I diabetes, and multiple sclerosis (MS). Hence, in recent years TLRs and associated signalling molecules have become attractive targets for their treatment and a number of inhibitors are currently in development or have progressed to clinical trials. Aberrant TLR activation is also thought to contribute to diseases with a strong association with inflammation such as cancer and atherosclerosis (reviewed in [711]).

One of the key questions to emerge from these studies is what factors drive TLR activation during the progression of disease. There is an increasing body of evidence to suggest that DAMP-mediated inflammation plays a vital role. It is also becoming apparent that PAMPs and DAMPs act in quite a different manner in order to stimulate an immune response. Here we review the mechanisms of DAMP recognition by TLRs, the signalling cascades, and the biological outcomes resulting from self TLR activation, focusing on the differences to non-self TLR activation. We also discuss the evidence that implicates endogenous molecules in pathological TLR activation and examine how blockade of DAMP action may be therapeutically beneficial. Understanding more about the differences between PAMP- and DAMP-induced inflammation may enable us to specifically target inappropriate, pathogenic inflammation whilst leaving the host defence intact.

2. Endogenous Activators of TLRs

The first report of a putative endogenous activator of TLRs dates back to 2000, when heat shock protein 60 (HSP60) was shown to induce cytokine synthesis through TLR4 activation [12]. In the same year necrotic cells were found to induce pro-inflammatory and tissue repair gene synthesis and cause DC maturation in a TLR2 dependent manner, as a result of the release of their intracellular contents [13, 14]. The list of endogenous TLR2 and 4 activators has expanded quickly and encompasses other intracellular molecules such as heat shock proteins including HSP70, Gp96 [1517], HSP22, and HSP72 [18, 19] and high-mobility group box-1 protein (HMGB1) [2022] as well as ECM molecules such as biglycan [23], tenascin-C [24], versican [25], and fragments of ECM molecules including oligosaccharides of hyaluronic acid (HA) [26] and heparan sulfate (HS) [27].

Notably, the list of TLRs activated by endogenous molecules is also expanding. For instance, TLR1 was shown for the first time to be required, along with TLR2, for the activation of professional antigen-presenting cells by β-defensin-3, a host-derived antimicrobial peptide [28]. Self-nucleic acids have also been described as endogenous danger signals, namely, mRNA recognised by TLR3 [29], single-stranded RNA (ssRNA) sensed by TLR7 and 8 [30], and IgG-chromatin complexes recognised by TLR9 [31]. Interestingly, emerging data support the activation of TLR7 and 8 by antiphospholipid antibodies (APL) isolated from patients with APL syndrome [32, 33], as has been also shown previously for TLR2 and 4 [3436]. A more complete list of DAMPs and their cognate TLRs can be found in Figure 1.

Figure 1
Endogenous TLR activators. TLRs are activated by damage-associated molecular patterns (DAMPs) including intracellular molecules released in the extracellular milieu by activated or necrotic cells and extracellular matrix molecules either upregulated ...

Given the use of E. coli to produce many of these endogenous molecules recombinantly, and the fact that most endogenous proteins activate TLR2 and 4, originally described as sensors of microbial products such as lipopolysaccharides (LPSs) and lipoproteins, the question of whether microbial contamination can partially or wholly account for DAMP activity remains a key issue. Erridge and Samani recently showed that apparent stimulation of TLR4 by saturated fatty acids was due to microbial contamination in their preparations of BSA [37]. In contrast, professional antigen-presenting cells that are not responsive to LPS were shown to be activated by necrotic cells indicating that LPS independent TLR4 activation does occur in response to endogenous ligands [38]. Similar to TLR2, TLR3 was also shown to recognize cells undergoing necrosis during acute inflammatory events, independently of viral infection [39]. Indeed, as details of the mechanisms of endogenous TLR ligand recognition emerge, it becomes clear that there are significant differences between PAMP and DAMP activation of TLRs. We discuss these differences in detail in the following sections of this review. In addition, the phenotype of mice with targeted deletions in a number of endogenous TLR activators confirms that removal of endogenous danger signals correlates with the effects of addition of exogenous DAMPs. Together these data indicate that DAMP activity is not reliant on the presence of contaminating PAMPs.

Recent data indicate that endogenous danger signals and microbial products can also cooperate in the induction of immune responses. Neither highly purified HSP preparations nor LPS alone at concentrations corresponding to those found in contaminated HSP preparations could induce pro-inflammatory cytokine production (reviewed in [4042]). Further studies showed that HSP60 and Gp96 can tightly bind to LPS in a saturable manner and enhance its biological activity, as well as that of the TLR2 ligand Pam3Cys [4345]. In the light of these results, the function of HSPs has been proposed to modulate early immune responses during infection by mediating a synergy between PAMPs and DAMPs. Similarly, HSP90 has also been implicated in the recognition of CpG DNA by TLR9 and the binding of HMGBs to nucleic acids is required for efficient recognition by TLR3, 7, and 9 [4648].

3. Mechanisms of TLR Activation by DAMPs versus PAMPs

There is an increasing body of evidence that demonstrates how exogenous and endogenous activation of TLRs is mediated and this reveals that, whilst there is some overlap in molecular machinery, DAMPs possess distinct mechanisms of action to PAMPs. These similarities and differences emerge below where we explore the mechanisms of PAMP and DAMP recognition by TLRs and the subsequent TLR signalling and biological outcomes.

3.1. Ligand Recognition by TLRs

3.1.1. Exogenous Ligand Recognition

TLRs interact with a wide variety of ligands ranging from proteins and lipoproteins to nucleic acids and saccharides, all of which are different in size and chemical properties. The extracellular domains (ECDs) of TLRs contain leucine-rich repeat (LRR) motifs that are responsible for PAMP recognition [49]. The crystal structures of three TLR ECD-ligand complexes have been solved. One structure shows that TLR3 interacts with hydrophilic double-stranded RNA (dsRNA) via surface-exposed sites [50]. A second structure shows TLR1-TLR2 heterodimers bound to the hydrophobic Pam3CSK4 lipopeptide that fits in an internal hydrophobic pocket [51]. Finally, the structure of the TLR4-MD-2-LPS complex shows that TLR4 employs the co-receptor MD-2 to recognise LPS and that no direct contacts between the receptor and the ligand take place [5254]. The latter structure also provided insights into the structure-activity relationship of the lipid A moiety of LPS. Not only the number of lipid chains [55, 56] but also the phosphate groups and their positioning in the lipid A are important factors affecting the immunological activity of LPS [53]. This suggests that even minor modifications to ligands may cause significant changes in the responses they generate.

These three crystal structures highlight three diverse modes of exogenous ligand recognition by TLRs involving TLR homo- and heterodimerization as well as direct TLR-ligand interactions or the use of co-receptors and accessory molecules. A number of accessory molecules have been shown to assist microbial recognition by TLRs. For instance, LPS is extracted from the bacterial membrane by the LPS-binding protein (LBP) after which it is transferred to CD14. Subsequent transfer from CD14 to an additional accessory molecule MD-2 then allows TLR4-mediated LPS recognition [57]. Interestingly, in the absence of MD-2, the LPS-dependent TLR4 signalling can be reconstituted by the mite dust allergen Der p 2, which has structural and functional homology with MD-2 and mimics the activity of MD-2 by presenting LPS to TLR4 [58, 59]. HMGB1 can also mediate LPS transfer to CD14 to initiate a TLR4-mediated pro-inflammatory response [60]. In B cells, the TLR-like molecule radioprotective 105 (RP105) forms a complex with the MD-2 homolog MD-1 and is essential for regulating TLR2 and 4-dependent antibody production to the ligands lipoproteins and LPS. Conversely, in macrophages and DCs, RP105/MD-1 acts as a TLR4 decoy receptor that, by interacting directly with the TLR4 signalling complex, inhibits the ability of the receptor to bind microbial ligands [61, 62]. Other accessory molecules bind directly to TLR ligands. CD14 facilitates LPS transfer to TLR4/MD-2 and, accordingly, in the absence of CD14 rough LPS cannot initiate the TRIF/TRAM pathway and smooth LPS cannot be detected at all [63, 64]. CD14 binds also to triacylated lipopeptides facilitating their recognition by TLR2/TLR1 complexes [65] and can enhance dsRNA-mediated TLR3 activation [66]. CD36 is a sensor of diacylated lipopeptides recognised by TLR2/TLR6 [67]. NAD(P)H oxidase 4 (Nox4) modulates the production of LPS-induced reactive oxygen species (ROS) by interacting with the cytoplasmic TIR domain of TLR4 [68, 69]. TLRs also cooperate with other families of receptors to recognise microbial ligands. TLR2 was shown to collaborate with dectin-1 in zymosan recognition [70] or with the macrophage receptor with collagenous structure (MARCO) in addition to CD14 to respond to TDM, a cell wall glycolipid from Mycobacterium tuberculosis [71]. Collectively these data point to specific and complex mechanisms at the basis of PAMP recognition, highlighted by the requirement of a number of distinct co-receptors and accessory molecules for individual ligands.

3.1.2. Endogenous Ligand Recognition by TLRs

No crystal structures of TLR-endogenous ligand complexes have been reported so far. Most of the proposed endogenous TLR activators have been shown to form complexes with TLRs in vitro by means of immunoprecipitation assays and functional cell-based assays or in vivo, taking advantage of mice deficient in TLRs or their adaptor proteins. Recently, FRET confocal microscopy and GFP fragment reconstitution have been proposed to study TLR interaction and measure distances between receptors in the range of molecular interactions [72]. This technique might be of great benefit in demonstrating and characterising endogenous ligand recognition by TLRs.

There exists circumstantial evidence that DAMPs and PAMPs may occupy the same or neighbouring binding sites on TLRs. For instance, surfactant protein A was shown to downregulate peptidoglycan and zymosan induced NFκB activation and TNFα secretion by binding to the extracellular domain of TLR2 in RAW 264.7 and alveolar macrophages [73, 74]. However, some DAMPs may utilize different binding sites; whilst the TLR4 mutations D299G and T399I prevent activation by LPS, these polymorphisms confer enhanced ability of TLR4 to respond to fibrinogen [75].

There is also evidence that DAMPs require different co-receptors and accessory molecules to PAMPs. Reviewing the proposed modes of endogenous ligand recognition leads to a rational classification of endogenous molecules based on the receptor, co-receptor(s), and accessory molecule(s) requirement for recognition by TLR(s) and subsequent cellular activation that is summarized in Figure 2. A first group of DAMPs requires both CD14 and MD-2. This includes both TLR2 and 4 agonists, such as HSP60, HSP70, and biglycan, as well as TLR4 activators such as oxidized LDL and S100 proteins [15, 23, 69, 76, 77]. A second group of DAMPs requires only CD14 as an accessory molecule and these are surfactant protein A and D and lactoferrin [7880]. A third group comprises DAMPs that have been shown to involve only MD-2 in their recognition by TLRs. Among these, Gp96 and HMGB1 activate TLR2 and 4, whereas fibronectin EDA (FNEDA) and saturated fatty acids activate TLR4 [17, 20, 22, 8186]. A fourth group includes DAMPs that use co-receptors or accessory molecules different from CD14 and MD-2. Biglycan was recently shown to induce the NLRP3/ASC inflammasome through activation of TLR2/4 and purinergic P2X4/P2X7 receptors [87]. Versican-induced responses require TLR2, TLR6, and CD14 [25]. HA dependent TLR4 activation involves CD44 in addition to MD-2 [88]. Autoantibodies against dsDNA and nucleosomes from SLE patients induce DC activation through TLR2 if bound to HMGB1 [89, 90]. Similarly, HMGB1 mediates the activation of plasmacytoid DCs and B cells through TLR9 by DNA-containing immune complexes through a mechanism involving the immunoglobulin superfamily member RAGE [46]. IgG2a-chromatin immune complexes require the synergistic engagement of IgM and TLR9 to activate B cells [31]. TLR7, 8, and TLR9 expressed by pDCs respond to self-RNA and -DNA respectively when coupled with the endogenous antimicrobial peptide LL37 [91, 92]. Furthermore, CD32 delivers DNA-containing immune complexes found in serum from SLE patients to intracellular lysosomes containing TLR9, leading to DC activation [89, 90]. Finally, B cells are activated by DNA- or RNA-associated autoantigens by combined B cell antigen receptor (BCR)/TLR9 or TLR7 engagement [93, 94]. This is a provisional list of endogenous activators and their accessory molecules that will certainly expand as we learn more about DAMP-TLR interactions. Collectively, these data indicate that several co-receptors and accessory molecules required for ligand recognition by TLRs are employed by both DAMPs and PAMPs. Further detailed investigation of how DAMPs are recognised by the cell is required to elucidate the precise structural organization of these receptor complexes. A signalling competent conformation of the receptor is required for TLRs to function; however it is not known whether the conformation induced by DAMPs is similar or distinct to that produced by microbial structures where sequential changes in receptor conformation occur upon ligand binding (reviewed in [95]).

Figure 2
Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular ...

3.2. TLR Signalling and Biological Outcomes

Ligand-induced receptor homo- or heterodimerization leads the cytoplasmic signalling domains of TLRs to dimerize. Despite diverse mechanisms of ligand interaction, PAMP-TLR complex crystal studies showed striking similarities in the organization of ligand-TLR dimer complexes that may apply to all TLRs. All three structures feature an “m”-shaped TLR dimeric architecture in which the C-terminal ends of the TLRs converge and, presumably, cause dimerization of the intracellular domains for signal initiation (reviewed in [97]). The resulting TIR-TIR complex initiates downstream signalling through recruitment of specific adaptor molecules. Five adaptors have been described so far: myeloid differentiation factor 88 (MyD88), MyD88-adaptor like (Mal), TIR domain-containing adaptor inducing IFN-beta (TRIF), TRIF-related adaptor molecule (TRAM), and sterile alpha and HEAT-Armadillo motifs (SARM) [98].

Depending on the adaptors recruited to the TLRs, two major intracellular signalling pathways can be activated by TLRs. The first, a MyD88-dependent pathway, is activated by all TLRs except TLR3. It involves the IL-1R-associated kinases (IRAK), IRAK-1 and IRAK-4, TNF receptor-associated factor 6 (TRAF-6), and mitogen-activated kinases (MAPK) and it culminates in the activation of the transcription factor NFκB via the IkB kinase (IKK) complex. In turn, NFκB mediates the transcription of pro-inflammatory cytokine genes. The second pathway, known as TRIF pathway, is independent of MyD88 and can be activated upon stimulation of TLR3 or 4. It leads to activation of the interferon-regulated factors (IRF) family of transcription factors via recruitment of TRIF and results in the synthesis of interferon (IFN).

TLR signalling pathways induced by endogenous molecules in different cell types are poorly investigated, but recent studies report usage of distinct adaptor molecules and induction of distinct signalling pathways downstream of TLRs when stimulated with exogenous or endogenous molecules. Activation of TLR4 by LPS can induce both TRIF and MyD88-dependent pathways. In contrast, we have shown that the endogenous TLR4 agonist tenascin-C signals via MyD88 [24]. Similarly, biglycan has been shown to signal through TLR2 and 4 in a MyD88-dependent manner [23].

TLR signalling results in the activation of transcription factors regulating the expression of specific genes whose products trigger various cellular responses. For example, NFκB, AP-1, and IRF5 control the expression of genes encoding inflammatory cytokines, whereas IRF3 and IRF7 induce the expression of type I IFN and IFN-inducible genes. Thus a large number of proteins are synthesised that mediate inflammatory and immune responses and include inflammatory cytokines such as IL-1, IL-6, TNFα, IL-12, IFNs, chemokines, adhesion molecules, costimulatory molecules, growth factors, tissue-degrading enzymes such as metalloproteinases, and enzymes that generate inflammatory mediators such as cyclo-oxygenase 2 and inducible nitric oxide synthase (iNOS).

Different microbial agents trigger multiple pathways in different cell types and induce the expression of distinct subset of genes [99103]. A detailed comparative analysis of the biological outcomes induced by different endogenous versus exogenous TLR molecules has not been performed. However, some crucial differences between host responses to endogenous versus microbial agents are emerging.

HMGB1 and LPS were shown to induce distinct patterns of gene expression in neutrophils. For instance, expression of monoamine oxidase B and the anti-apoptosis protein Bcl-xl was increased in neutrophils by HMGB1 but not by LPS. Furthermore, whilst the cytokine expression profile induced by HMGB1 versus LPS was similar, a slower induction of TNFα mRNA occurred upon LPS stimulation compared to HMGB1 [20, 104, 105]. HSP60 and LPS, in addition to synergistically enhancing IL-12p40 and IFNγ production in murine macrophages and in mHSP60-expressing COS1 cells, were shown to differentially activate APC function. Indeed, only HSP60 was able to stimulate the production of IFNα in peritoneal macrophages and bone marrow-derived DCs and IFNα release was not further increased by HSP60/LPS complexes [43]. Hyaluronan fragments generated following injury were reported to induce inflammatory responses distinct from LPS. A microarray analysis performed on the mouse alveolar macrophage cell line (MH-S) generated a list of genes that respond differently to hyaluronan and LPS. For instance, MMP13, TGF-β2, SOCS3, and other genes were induced exclusively by hyaluronan. There were also major differences in the cytokine profile induced. While some cytokines including TNFα, MCP-1, and RANTES were equally induced by both ligands, others, such as granulocyte macrophage-colony stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and IL-1α, were significantly different [88]. We have shown that tenascin-C stimulated pro-inflammatory cytokine synthesis in primary human macrophages and synovial fibroblasts in a cell type specific manner, which was significantly different from LPS. Tenascin-C dose dependently induced TNFα, IL-6, and IL-8 production in human macrophages. However, it only induced IL-6 synthesis in synovial fibroblasts, whereas LPS induced both IL-6 and IL-8 [24]. Further investigation is required to fully define the differences in signalling pathways and gene expression induced by endogenous versus exogenous TLR activators.

4. DAMPs and Disease

DAMPs are key danger signals that alert the organism to tissue damage and initiate the process of tissue repair. However, in addition to this physiological role in the response to tissue injury, there is evidence which indicates that endogenous TLR activators also contribute to the pathogenesis of many inflammatory and autoimmune diseases that are characterized by aberrant TLR activation.

4.1. High Levels of DAMPs Are Associated with Human Inflammatory Disease

The etiology of many inflammatory and autoimmune diseases is unclear; the initiating stimuli are often not well defined and the reasons why the mechanisms that ordinarily control the immune response fail are not known. However, it is clear that these diseases are characterized by an extremely destructive tissue environment. Accordingly, high levels of DAMPs occur locally and/or systemically in many of these conditions. For example, a wide range of endogenous TLR activators, including heat shock proteins, HMGB1, host DNA, fibrinogen, FNEDA, and tenascin-C, are observed in synovia of RA patients but not in synovia from normal joints or non-inflamed synovia from osteoarthritis (OA) patients [106112]. High levels of HMGB1 and tenascin-C circulate in the serum of septic patients [113, 114], and high serum concentrations of DNA-containing immune complexes are associated with SLE [46], including nucleosome-HMGB1 complexes [90, 115]. In addition, elevated levels of low MW HA fragments are reported in the bronchial alveolar lavage fluid and serum of patients with inflammatory lung diseases [116118]. In many cases levels of endogenous TLR activators are indicative of disease activity; elevated levels of extracellular HMGB1 localize specifically to active lesions of multiple sclerosis (MS) patients and correlate with active inflammation [119]. Furthermore, the S100 family of calcium binding proteins have long been reliable biomarkers of inflammation in a wide variety of diseases; for example, both MRP8 and MRP14 levels in the RA synovium and synovial fluid correlate with disease activity to a degree greater than levels of C-reactive protein (reviewed in [120]). Many endogenous TLR activators are also overexpressed in tumor cells. Figure 3 summarises some of the diseases with which endogenous TLR activators are associated.

Figure 3
DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.

4.2. Administration of Exogenous DAMPs Induces Inflammation In Vivo

Further support of a role for endogenous TLR activators in driving disease derives from in vivo studies using experimental models of inflammatory disease. Levels of many DAMPs are elevated during the pathogenesis of numerous diseases in rodent models. In addition, delivery of exogenous DAMPs promotes inflammation in vivo via activation of TLRs. Intra-articular injection of the TLR4 activators FNEDA or tenascin-C induces joint inflammation in wild type but not in TLR4 null mice [24, 86]. Systemic injection of HS causes lethal sepsis, similar to that induced by LPS or zymosan, in wild type but not in TLR4 null mice [121]. Furthermore, DNA released from necrotic hepatocytes stimulates cytokine synthesis via activation of TLR9 during murine acetaminophen-induced liver injury [122]. These and other studies are summarized in Table 1. In addition, many DAMPs can act as adjuvants; this has recently been comprehensively reviewed by Kono and Rock [6]. For example, purified genomic dsDNA boosted both antibody and CD8+ T cell responses in mice when injected with antigen [123]. Likewise lactoferrin, defensins, low MW HA, and HMGB1 all exhibit adjuvant properties in vivo [124127]. Together these data show that many endogenous TLR activators exhibit pro-inflammatory properties in vivo.

Table 1
DAMPs induce disease in vivo. Administration of DAMPs to rodents either intra-articularly (i.a.), intracerebroventricularly (i.c.), intraperitoneally (i.p.), intratracheally (i.t.), or intravenously (i.v.) can provoke pathological inflammation in vivo ...

4.3. Inhibition of DAMP Action In Vivo Ameliorates Disease

Whilst many DAMPs can induce TLR dependent inflammation in vivo, this does not necessarily demonstrate that these molecules are important in the progression of disease. This evidence has come from mice that do not express specific endogenous TLR activators (Table 2) and studies showing that inhibition of DAMP function can ameliorate disease in vivo (Table 3) and we review these data below.

Table 2
Targeted deletion of DAMPs protects from experimental disease. Mice which do not express certain DAMPs exhibit reduced symptoms of inflammatory disease or tumor metastasis in vivo.
Table 3
Manipulation of DAMP function ameliorates experimental disease. Therapeutic blockade of DAMP function, for example, using monoclonal or polyclonal antibodies (mAb, pAb) or specific inhibitors or silencing DAMP expression by siRNA can reduce disease progression ...

4.3.1. Targeted Deletion of DAMPs Protects from Inflammatory Disease

Biglycan null mice have a considerable survival benefit in LPS-induced sepsis due to reduced TLR2 and 4 dependent cytokine synthesis, cellular infiltration into tissues [23], and lower levels of active caspase-1 and mature IL-1β in the kidney, lung, and circulation [87]. We have shown that tenascin-C null mice are protected from persistent joint inflammation and tissue destruction during antigen-induced arthritis [24]. In addition, mice lacking MRP8/MRP14 complexes are protected from endotoxin-induced lethal shock and E. coli-induced abdominal sepsis [140, 143] and exhibit reduced lesion volume, brain swelling, and inflammatory cell infiltration during cerebral ischemia [142]. Furthermore, consistent with their enhanced expression during myocardial infarction, mice that lack MRP-8/14 complexes exhibited reduced inflammatory cell infiltration upon experimental arterial injury and attenuated atherosclerotic lesions and macrophage accumulation in plaques compared with mice deficient in apolipoprotein E alone [141].

4.3.2. DAMP Antagonists Ameliorate Disease

The fact that blockade of DAMP function ameliorates disease in vivo further supports a role for endogenous TLR activators in inflammatory disease. The best example of how this can be achieved is with HMGB1 (reviewed in [170174]), although manipulation of other DAMPs including HA, neutrophil elastase (NE), and versican can all protect against disease (Table 3). DAMPs comprise an enormously diverse subset of molecules. As such there exists a number of different mechanisms to prevent their inflammatory action, some of which are described below.

(i) Blockade of TLR Activation —

One strategy that has proved effective is to manipulate the function of individual DAMPs by preventing TLR activation at the cell surface. Administration of polyclonal anti-HMGB1 antibodies or the DNA-binding A box of HMGB1, a competitive inhibitor of the pro-inflammatory B box, can reverse the lethality of established sepsis [114, 153, 154] and ameliorate collagen-induced arthritis in rodents (reviewed in [161]). However, whilst some reports demonstrate that monoclonal anti-HMGB1 antibodies are efficacious preventing organ damage in experimental models of sepsis [155], others suggest that monoclonal antibodies are not effective in suppressing arthritic disease in vivo [175]. This may be due to the multivalent nature of the mode of action of HMGB1. One alternative approach may be to use synthetic, bent oligonucleotides that have a high affinity for HMGB1, and suppress HMGB1-induced proliferation and migration of smooth muscle cells in vitro [176]. Another approach may be the use of an engineered mutant fragment, HMGB1 Mut (102–105) carrying two glycine substitutions, that decreased TNFα  release induced by the full-length HMGB1 protein in human monocyte cultures [177]. In addition, the N-terminal domain of thrombomodulin, an endothelial anticoagulant cofactor, exerts anti-inflammatory effects in a model of lethal endotoxemia partly by binding to and sequestering HMGB1 [178].

(ii) Prevention of DAMP Accumulation —

DAMPs can be generated by release from necrotic cells, secretion from activated cells, cleavage of larger molecules, or specific upregulation upon tissue injury. Manipulation of tissue levels of DAMPs may provide another window of therapeutic opportunity. Indeed, ethyl pyruvate, stearoyl lysophosphatidylcholine, and nicotine have been shown to be efficacious in ameliorating experimental sepsis by preventing HMGB1 release during experimental sepsis [156158]. However, the mechanism by which they do so is unclear and these compounds are likely also to affect numerous other cell processes. HMGB1 is released from cells by two distinct mechanisms: it is liberated from cells undergoing necrosis [179], or it is hyperacetylated and then actively secreted from stimulated cells. This non-classical secretion pathway is distinct from the passage through the ER and Golgi taken by signal tagged proteins, instead requiring the microtubule cytoskeleton [180]. Other DAMPs including the S100 proteins are also secreted in the same way [181] and targeting this pathway therefore may potentially offer a means to modulate the release of intracellular DAMPs.

One class of DAMPs comprises ECM fragments generated by release from intact matrices. Inhibition of this process has been demonstrated; for example, release of immune-stimulatory HS fragments from the ECM in vivo can be mediated by the proteolytic action of elastase [182]. Injection of elastase into the peritoneal cavity of mice caused the release of HS and induced sepsis, nearly as effectively as direct injection of HS or LPS [121]. Thus therapeutic measures aimed at blocking elastase could reduce the production of endogenous TLR4 activators. Indeed, pre-treatment with NE inhibitor before induction of hepatic ischemia-reperfusion injury ameliorated liver damage [168]. HS fragments are also generated upon ECM oxidation by reactive oxygen species (ROS). Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that protects the lung from oxidant-mediated inflammation. One way in which it does this is to protect HS from oxidative fragmentation; bronchoalveolar lavage fluid from EC-SOD knockout mice after asbestos exposure showed increased HS shedding from the lung parenchyma [183]. An alternative strategy may be to alter the balance of immune-silent intact ECM molecules versus immune-stimulatory fragments either directly or indirectly. Specific over expression of high MW HA in the lung has been achieved using transgenic mice that constitutively express HA synthase. These mice showed that improved survival and decreased apoptosis during bleomycin induce lung inflammation [145].

Finally, for DAMPs whose expression is specifically upregulated during inflammation it may be possible to manipulate this induction of expression. Indeed, knockdown of versican expression in Lewis lung carcinoma cell lines (LLC) ablated their tumorigenic capability, promoting mouse survival and reduced metastasis, whilst overexpression of versican in LLC lines with low innate metastatic potential increased lung metastasis [25].

Together these data indicate that endogenous TLR activators significantly contribute to driving inflammatory disease in vivo and suggest that targeting this method of TLR activation may potentially be of therapeutic value in combating disease.

5. Conclusions and Perspectives: Targeting DAMPs in the Clinic?

Current strategies in clinical development for TLR blockade include (1) global blockade of individual TLR function using neutralizing antibodies, soluble TLR extracellular domains (ECDs), natural antagonists, and small molecule inhibitors, (2) inhibition of signalling pathways-activated downstream of TLR stimulation using small molecules to target MyD88/TRAF/IRAK complex formation, MAPK, or IKK activity, or (3) using PAMP antagonists such as LPS inhibitors. Some of these compounds have reached phase II clinical trials and the results are currently awaited, whilst others, particularly those targeting common signalling pathways such as MAPK, have proved to be of limited efficacy (reviewed in [11]).

Suppressing DAMP activation of TLRs offers a host of new potential targets for treating inflammatory diseases that may be viable alternatives to current approaches. Evidence that blockade of these mediators can ameliorate disease in human studies is beginning to emerge. Hyaluronate improves pain and prostaglandin E (PGE) levels in patients with RA [184], transfer of HSP-specific regulatory T cells inhibits inflammation in animal models of arthritis and exhibited promising results in preliminary clinical trials [185], HMGB1 antibodies prevent the activation of cells by serum from SLE patients [46], and the neutrophil elastase inhibitor sivelestat improves the mortality rate of patients with sepsis [186, 187]. By carefully choosing a target unique to the response to tissue damage, and not to pathogen mediated activation of the immune response, this strategy may have the additional advantage of leaving the host response to infection intact. Given the evidence that supports the idea that distinct molecular machinery is required for DAMP activation of TLRs, another strategy would be to block co-receptors or accessory molecules essential for DAMP activation. In addition a comparative analysis of adaptors, kinases, and transcription factors involved in signalling activated by DAMPs versus PAMPs may highlight key differences that, if selectively targeted, could lead to specific therapies engineered to silence danger signals without compromising the host immune defence.

We have highlighted here the possible levels of intervention in DAMP activation of TLR-mediated inflammation, namely, manipulating DAMP activation of TLRs or controlling tissue level of DAMPs. Whilst these strategies are efficacious in preventing experimental disease, there is also evidence that preconditioning with DAMPs can have the same effect. Administration of small doses of HMGB1 one hour prior to induction of hepatic reperfusion injury protected from liver damage and reduced serum TNFα and IL-6 levels via inhibition of TLR4 signalling [188, 189] and lactoferrin can protect from lethal E.coli injection [190].

It is apparent that low tissue levels of DAMPs are beneficial during tissue repair to induce a resolvable, physiological immune response. In contrast, high levels of DAMPs are generated during chronic inflammation. We propose a situation where a damage chain reaction occurs: increasing levels of pro-inflammatory DAMPs create more tissue damage which significantly amplifies the tissue levels of DAMPs which go on to create yet more tissue damage ad infinitum. These tissue levels of DAMPs become harmful and mediate a non-resolving perpetual inflammatory state (Figure 4). Thus targeting DAMP-mediated activation of TLRs may block this chronic inflammatory loop, although it will be important to assess whether total blockade of DAMP function will compromise tissue repair to any deleterious extent.

Figure 4
The “damage chain reaction.” Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating ...

In addition, in the destructive milieu that occurs during inflammatory disease there are likely to be high levels of many DAMPs. Working out which are keys to disease pathogenesis may not be a trivial matter, and combinations of inhibitors may be needed to successfully dampen down endogenously driven inflammation. Alternatively, hierarchies may exist amongst DAMPs such as those that exist for inflammatory cytokines, for example, where TNFα induces a cascade of cytokine synthesis. Indeed, low MW HA induces β-defensin2 via TLR2 and 4 activation in murine keratinocytes ex vivo and in vivo [191]. These DAMPs may be key targets to prevent the induction of an autocrine loop of inflammation. Unravelling potential hierarchies amongst DAMPs represents a major challenge for future investigations. These may be aided by approaches such as microarray and deep sequencing technologies, as well as proteomewide screening, to enable the comparison of the global effects of different DAMPs on inflammatory gene expression. Likewise, examining the stimuli that induce DAMP expression or release upon tissue injury will be important in establishing a “chain of command” of DAMP action. In parallel, the development of validated reagents and tools which serve to ablate the expression or function of individual DAMPS will yield key information about redundancy and co-dependency.

The threshold of DAMP(s) required to induce disease may vary upon the duration and degree of host tissue damage. However, current knowledge about the kinetics of expression or release of DAMPs and their turnover during disease progression is limited. Indeed, on one hand, validated commercial assays for measuring various endogenous danger signals are often unavailable or prohibitively expensive. On the other hand, access to patient specimens and pathological data is in many cases restricted. Thus, the correlation between degree of tissue damage and levels of DAMP(s) is either unknown or limited to small sample size, often representative of end stage of disease. The threshold of DAMPs required to trigger chronic inflammation may also depend on a variety of host genetic factors, including single-nucleotide polymorphisms (SNPs), which can affect how humans respond to injury and develop disease. Examining the role of DAMPs within the context of different genetic backgrounds will also be key to dissecting out their role in inflammatory disease. The use of larger patient sample sizes including diverse genetic populations and a befitting proportion of male and females will be vital. In addition, the development of mouse strains with much greater DNA diversity than strains traditionally employed [192] may provide mice with combinations of different traits that more closely reflect the genomic variations of humans in preclinical studies. We expect that the next few years will provide a much more concrete picture of how DAMPs link tissue damage to chronic inflammation as an increasing number of tools become available.

Finally, a normal wound healing response does not typically lead to chronic inflammation. This is, in part, because a number of mechanisms exist to negatively regulate TLR activation. These include the release of soluble decoy TLR receptors, intracellular inhibitory molecules such as IRAK-M, SOCS1, Tam family kinases, and transmembrane regulators such as SIGIRR (reviewed in [8, 193]). Viruses have also evolved mechanisms to target adapters in TLR signalling: A46R from vaccinia virus, which sequesters MyD88, Mal, Trif, and Tram [194], and NS3/4A from hepatitis C virus, which degrades Trif [195]. In addition, recently, microRNA, miR-147, whose expression is induced upon stimulation of multiple TLRs, was shown to attenuate TLR stimulation-induced-inflammatory response in macrophages [196].

However, these pathways do not appear to discriminate between distinct methods of TLR stimulation and act on DAMP- and PAMP-mediated activation alike. Chen et al. recently identified one way in which specific activation of TLRs by DAMPs, but not PAMPs, may be inhibited (reviewed in [197]). CD24, or heat stable antigen, is a GPI anchored protein that binds to DAMPs such as HMGB1, hsp70, and hsp90 in order to suppress their activation of inflammatory signalling pathways. CD24 null mice exhibit increased susceptibility to DAMP-, but not PAMP, induced inflammation. This is mediated at least in part through CD24 association with Siglec-10/G causing activation of associated phosphatases which are proposed to repress DAMP-initiated signalling. Dysfunction of this pathway might contribute to the etiology of autoimmune diseases and likewise may offer a means to selectively inhibit DAMP activity [198]. In addition, sTLR2 can blunt immune responses without preventing microbial recognition: mice injected with Gram positive bacteria together with sTLR2 exhibited reduced inflammatory cytokine levels and cell migration but this did not compromise their ability to clear live Gram-positive bacteria-induced infection [199]. As such enhancing naturally suppressive mechanisms may also be a viable strategy for reducing inflammation.

Thus DAMPs appear to be a double-edged sword. While being vital for tissue repair, they also play a role in the pathogenesis of many inflammatory and autoimmune diseases that feature aberrant TLR activation. In these diseases harmful stimuli cause tissue damage; in an attempt of tissue healing, inflammatory responses are initiated and generate DAMPs that induce an autocrine loop of inflammation. Understanding why the natural mechanisms that keep DAMP-mediated inflammation in check fail in disease, as well as dissecting out which mechanisms of TLR activation and signalling are unique to DAMPs, may enlighten our approach to engineering targeted and efficacious therapies designed to dampen inflammation.


The authors are supported by the Arthritis Research Campaign and a Medical Research Council New Investigators Research Grant. They thank Professor Nick Gay and Dr. Nikki Horwood for critically reading this manuscript.


1. Matzinger P. Tolerance, danger, and the extended family. Annual Review of Immunology. 1994;12:991–1045. [PubMed]
2. Beutler B. Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease. Immunological Reviews. 2007;220(1):113–128. [PubMed]
3. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology. 2007;81(1):1–5. [PubMed]
4. Gordon S. Pattern recognition receptors: doubling up for the innate immune response. Cell. 2002;111(7):927–930. [PubMed]
5. Medzhitov R, Janeway CA., Jr. Decoding the patterns of self and nonself by the innate immune system. Science. 2002;296(5566):298–300. [PubMed]
6. Kono H, Rock KL. How dying cells alert the immune system to danger. Nature Reviews Immunology. 2008;8(4):279–289. [PMC free article] [PubMed]
7. Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM. Toll-like receptors in inflammation, infection and cancer. International Immunopharmacology. 2007;7(10):1271–1285. [PubMed]
8. Liew FY, Xu D, Brint EK, O’Neill LAJ. Negative regulation of Toll-like receptor-mediated immune responses. Nature Reviews Immunology. 2005;5(6):446–458. [PubMed]
9. Lotze MT, Zeh HJ, Rubartelli A, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunological Reviews. 2007;220(1):60–81. [PubMed]
10. Mantovani A. Cancer: inflaming metastasis. Nature. 2009;457(7225):36–37. [PubMed]
11. Midwood KS, Piccinini AM, Sacre S. Targeting Toll-like receptors in autoimmunity. Current Drug Targets. 2009;10(11):1139–1155. [PubMed]
12. Ohashi K, Burkart V, Flohé S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. Journal of Immunology. 2000;164(2):558–561. [PubMed]
13. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. International Immunology. 2000;12(11):1539–1546. [PubMed]
14. Li M, Carpio DF, Zheng Y, et al. An essential role of the NF-κB/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. Journal of Immunology. 2001;166(12):7128–7135. [PubMed]
15. Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: role of Toll-like receptor (TLR) 2 and TLR4. Journal of Biological Chemistry. 2002;277(17):15028–15034. [PubMed]
16. Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. Journal of Biological Chemistry. 2002;277(17):15107–15112. [PubMed]
17. Vabulas RM, Braedel S, Hilf N, et al. The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. Journal of Biological Chemistry. 2002;277(23):20847–20853. [PubMed]
18. Roelofs MF, Boelens WC, Joosten LAB, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. Journal of Immunology. 2006;176(11):7021–7027. [PubMed]
19. Wheeler DS, Chase MA, Senft AP, Poynter SE, Wong HR, Page K. Extracellular Hsp72, an endogenous DAMP, is released by virally infected airway epithelial cells and activates neutrophils via Toll-like receptor (TLR)-4. Respiratory Research. 2009;10:p. 31. [PMC free article] [PubMed]
20. Park JS, Svetkauskaite D, He Q, et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. Journal of Biological Chemistry. 2004;279(9):7370–7377. [PubMed]
21. Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Molecular Medicine. 2008;14(7-8):476–484. [PubMed]
22. Park JS, Gamboni-Robertson F, He Q, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. American Journal of Physiology. 2006;290(3):C917–C924. [PubMed]
23. Schaefer L, Babelova A, Kiss E, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. Journal of Clinical Investigation. 2005;115(8):2223–2233. [PubMed]
24. Midwood K, Sacre S, Piccinini AM, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature Medicine. 2009;15(7):774–780. [PubMed]
25. Kim S, Takahashi H, Lin W-W, et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature. 2009;457(7225):102–106. [PMC free article] [PubMed]
26. Termeer C, Benedix F, Sleeman J, et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. Journal of Experimental Medicine. 2002;195(1):99–111. [PMC free article] [PubMed]
27. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. Journal of Immunology. 2002;168(10):5233–5239. [PubMed]
28. Funderburg N, Lederman MM, Feng Z, et al. Human β-defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(47):18631–18635. [PubMed]
29. Karikó K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. Journal of Biological Chemistry. 2004;279(13):12542–12550. [PubMed]
30. Vollmer J, Tluk S, Schmitz C, et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. Journal of Experimental Medicine. 2005;202(11):1575–1585. [PMC free article] [PubMed]
31. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416(6881):603–607. [PubMed]
32. Hurst J, Prinz N, Lorenz M, et al. TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1β and caspase-1 in monocytes and dendritic cells. Immunobiology. 2009;214(8):683–691. [PubMed]
33. Döring Y, Hurst J, Lorenz M, et al. Human antiphospholipid antibodies induce TNFα in monocytes via Toll-like receptor 8. Immunobiology. 2010;215(3):230–241. [PubMed]
34. Satta N, Dunoyer-Geindre S, Reber G, et al. The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies. Blood. 2007;109(4):1507–1514. [PubMed]
35. Mulla MJ, Brosens JJ, Chamley LW, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. American Journal of Reproductive Immunology. 2009;62(2):96–111. [PMC free article] [PubMed]
36. Pierangeli SS, Vega-Ostertag ME, Raschi E, et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Annals of the Rheumatic Diseases. 2007;66(10):1327–1333. [PMC free article] [PubMed]
37. Erridge C, Samani NJ. Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29(11):1944–1949. [PubMed]
38. Lee K-M, Seong S-Y. Partial role of TLR4 as a receptor responding to damage-associated molecular pattern. Immunology Letters. 2009;125(1):31–39. [PubMed]
39. Cavassani KA, Ishii M, Wen H, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. Journal of Experimental Medicine. 2008;205(11):2609–2621. [PMC free article] [PubMed]
40. Tsan M-F, Gao B. Endogenous ligands of Toll-like receptors. Journal of Leukocyte Biology. 2004;76(3):514–519. [PubMed]
41. Tsan M-F, Gao B. Heat shock proteins and immune system. Journal of Leukocyte Biology. 2009;85(6):905–910. [PubMed]
42. Radsak MP, Hilf N, Singh-Jasuja H, et al. The heat shock protein Gp96 binds to human neutrophils and monocytes and stimulates effector functions. Blood. 2003;101(7):2810–2815. [PubMed]
43. Osterloh A, Kalinke U, Weiss S, Fleischer B, Breloer M. Synergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide. Journal of Biological Chemistry. 2007;282(7):4669–4680. [PubMed]
44. Warger T, Hilf N, Rechtsteiner G, et al. Interaction of TLR2 and TLR4 ligands with the N-terminal domain of Gp96 amplifies innate and adaptive immune responses. Journal of Biological Chemistry. 2006;281(32):22545–22553. [PubMed]
45. Habich C, Kempe K, Van Der Zee R, et al. Heat shock protein 60: specific binding of lipopolysaccharide. Journal of Immunology. 2005;174(3):1298–1305. [PubMed]
46. Tian J, Avalos AM, Mao S-Y, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunology. 2007;8(5):487–496. [PubMed]
47. Bandholtz L, Guo Y, Palmberg C, et al. Hsp90 binds CpG oligonucleotides directly: implications for Hsp90 as a missing link in CpG signaling and recognition. Cellular and Molecular Life Sciences. 2003;60(2):422–429. [PubMed]
48. Yanai H, Ban T, Wang Z, et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462(7269):99–103. [PubMed]
49. Medzhitov R. Toll-like receptors and innate immunity. Nature Reviews Immunology. 2001;1(2):135–145. [PubMed]
50. Liu L, Botos I, Wang Y, et al. Structural basis of Toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320(5874):379–381. [PMC free article] [PubMed]
51. Jin MS, Kim SE, Heo JY, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130(6):1071–1082. [PubMed]
52. Kim HM, Park BS, Kim J-I, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130(5):906–917. [PubMed]
53. Park BS, Song DH, Kim HM, Choi B-S, Lee H, Lee J-O. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009;458(7242):1191–1195. [PubMed]
54. Miyake K. Roles for accessory molecules in microbial recognition by Toll-like receptors. Journal of Endotoxin Research. 2006;12(4):195–204. [PubMed]
55. Rossignol DP, Lynn M. TLR4 antagonists for endotoxemia and beyond. Current Opinion in Investigational Drugs. 2005;6(5):496–502. [PubMed]
56. Teghanemt A, Zhang D, Levis EN, Weiss JP, Gioannini TL. Molecular basis of reduced potency of underacylated endotoxins. Journal of Immunology. 2005;175(7):4669–4676. [PubMed]
57. Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. Journal of Experimental Medicine. 1999;189(11):1777–1782. [PMC free article] [PubMed]
58. Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nature Medicine. 2009;15(4):410–416. [PMC free article] [PubMed]
59. Trompette A, Divanovic S, Visintin A, et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457(7229):585–588. [PMC free article] [PubMed]
60. Youn JH, Oh YJ, Kim ES, Choi JE, Shin J-S. High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-α production in human monocytes. Journal of Immunology. 2008;180(7):5067–5074. [PubMed]
61. Nagai Y, Kobayashi T, Motoi Y, et al. The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes. Journal of Immunology. 2005;174(11):7043–7049. [PubMed]
62. Divanovic S, Trompette A, Atabani SF, et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunology. 2005;6(6):571–578. [PMC free article] [PubMed]
63. Latz E, Visintin A, Lien E, et al. Lipopolysaccharide rapidly traffics to and from the golgi apparatus with the Toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. Journal of Biological Chemistry. 2002;277(49):47834–47843. [PubMed]
64. Jiang Z, Georgel P, Du X, et al. CD14 is required for MyD88-independent LPS signaling. Nature Immunology. 2005;6(6):565–570. [PubMed]
65. Nakata T, Yasuda M, Fujita M, et al. CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the receptor complex of Toll-like receptors 2 and 1 without binding to the complex. Cellular Microbiology. 2006;8(12):1899–1909. [PubMed]
66. Lee H-K, Dunzendorfer S, Soldau K, Tobias PS. Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity. 2006;24(2):153–163. [PubMed]
67. Hoebe K, Georgel P, Rutschmann S, et al. CD36 is a sensor of diacylglycerides. Nature. 2005;433(7025):523–527. [PubMed]
68. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae YS. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-κB. Journal of Immunology. 2004;173(6):3589–3593. [PubMed]
69. Park HS, Chun JN, Jung HY, Choi C, Bae YS. Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells. Cardiovascular Research. 2006;72(3):447–455. [PubMed]
70. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. Journal of Experimental Medicine. 2003;197(9):1107–1117. [PMC free article] [PubMed]
71. Bowdish DME, Sakamoto K, Kim M-J, et al. MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and mycobacterium tuberculosis. PLoS Pathogens. 2009;5(6) Article ID e1000474. [PMC free article] [PubMed]
72. Horvath G, Young S, Latz E. Toll-like receptor interactions imaged by FRET microscopy and GFP fragment reconstitution. Methods in Molecular Biology. 2009;517:33–54. [PubMed]
73. Murakami S, Iwaki D, Mitsuzawa H, et al. Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-α secretion in U937 cells and alveolar macrophages by direct interaction with Toll-like receptor 2. Journal of Biological Chemistry. 2002;277(9):6830–6837. [PubMed]
74. Sato M, Sano H, Iwaki D, et al. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-α secretion are down-regulated by lung collectin surfactant protein A. Journal of Immunology. 2003;171(1):417–425. [PubMed]
75. Hodgkinson CP, Patel K, Ye S. Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. Thrombosis and Haemostasis. 2008;100(2):301–307. [PubMed]
76. Miller YI, Viriyakosol S, Binder CJ, Feramisco JR, Kirkland TN, Witztum JL. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. Journal of Biological Chemistry. 2003;278(3):1561–1568. [PubMed]
77. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA. Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. Journal of Immunology. 2000;164(1):13–17. [PubMed]
78. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M. Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. Journal of Immunology. 2002;168(12):5989–5992. [PubMed]
79. Ohya M, Nishitani C, Sano H, et al. Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide. Biochemistry. 2006;45(28):8657–8664. [PubMed]
80. Curran CS, Demick KP, Mansfield JM. Lactoferrin activates macrophages via TLR4-dependent and—independent signaling pathways. Cellular Immunology. 2006;242(1):23–30. [PubMed]
81. Okamura Y, Watari M, Jerud ES, et al. The extra domain a of fibronectin activates Toll-like receptor 4. Journal of Biological Chemistry. 2001;276(13):10229–10233. [PubMed]
82. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. Journal of Clinical Investigation. 2006;116(11):3015–3025. [PubMed]
83. de Graaf R, Kloppenburg G, Kitslaar PJHM, Bruggeman CA, Stassen F. Human heat shock protein 60 stimulates vascular smooth muscle cell proliferation through Toll-like receptors 2 and 4. Microbes and Infection. 2006;8(7):1859–1865. [PubMed]
84. Koh J-M, Lee Y-S, Kim YS, et al. Heat shock protein 60 causes osteoclastic bone resorption via Toll-like receptor-2 in estrogen deficiency. Bone. 2009;45(4):650–660. [PubMed]
85. Cohen-Sfady M, Nussbaum G, Pevsner-Fischer M, et al. Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway. Journal of Immunology. 2005;175(6):3594–3602. [PubMed]
86. Gondokaryono SP, Ushio H, Niyonsaba F, et al. The extra domain A of fibronectin stimulates murine mast cells via Toll-like receptor 4. Journal of Leukocyte Biology. 2007;82(3):657–665. [PubMed]
87. Babelova A, Moreth K, Tsalastra-Greul W, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via Toll-like and P2X receptors. Journal of Biological Chemistry. 2009;284(36):24035–24048. [PMC free article] [PubMed]
88. Taylor KR, Yamasaki K, Radek KA, et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. Journal of Biological Chemistry. 2007;282(25):18265–18275. [PubMed]
89. Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, Luster AD. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. Journal of Clinical Investigation. 2005;115(2):407–417. [PMC free article] [PubMed]
90. Urbonaviciute V, Fürnrohr BG, Meister S, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. Journal of Experimental Medicine. 2008;205(13):3007–3018. [PMC free article] [PubMed]
91. Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564–569. [PubMed]
92. Ganguly D, Chamilos G, Lande R, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. Journal of Experimental Medicine. 2009;206(9):1983–1994. [PMC free article] [PubMed]
93. Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. Journal of Experimental Medicine. 2005;202(9):1171–1177. [PMC free article] [PubMed]
94. Viglianti GA, Lau CM, Hanley TM, Miko BA, Shlomchik MJ, Marshak-Rothstein A. Activation of autoreactive B cells by CpG dsDNA. Immunity. 2003;19(6):837–847. [PubMed]
95. Gay NJ, Gangloff M. Structure and function of Toll receptors and their ligands. Annual Review of Biochemistry. 2007;76:141–165. [PubMed]
96. Mollen K, Mollen K, Kaczorowski D, et al. MD2 and CD14 mediate toll-like receptor 4 (TLR4) activation by high mobility group box 1 (HMGB1) Journal of the American College of Surgeons. 2007;205(3, supplement):p. S28.
97. Jin MS, Lee J-O. Structures of the Toll-like receptor family and its ligand complexes. Immunity. 2008;29(2):182–191. [PubMed]
98. Kenny EF, O’Neill LAJ. Signalling adaptors used by Toll-like receptors: an update. Cytokine. 2008;43(3):342–349. [PubMed]
99. Hirschfeld M, Weis JJ, Toshchakov V, et al. Signaling by Toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infection and Immunity. 2001;69(3):1477–1482. [PMC free article] [PubMed]
100. Jones BW, Heldwein KA, Means TK, Saukkonen JJ, Fenton MJ. Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages. Annals of the Rheumatic Diseases. 2001;60(supplement 3):iii6–iii12. [PMC free article] [PubMed]
101. Agrawal S, Agrawal A, Doughty B, et al. Cutting edge: different Toll-Like receptor agonists instruct ddendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. Journal of Immunology. 2003;171(10):4984–4989. [PubMed]
102. Barr TA, Brown S, Ryan G, Zhao J, Gray D. TLR-mediated stimulation of APC: distinct cytokine responses of B cells and dendritic cells. European Journal of Immunology. 2007;37(11):3040–3053. [PMC free article] [PubMed]
103. Lundberg AM, Drexler SK, Monaco C, et al. Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Blood. 2007;110(9):3245–3252. [PubMed]
104. Park JS, Arcaroli J, Yum H-K, et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein. American Journal of Physiology. 2003;284(4):C870–C879. [PubMed]
105. Silva E, Arcaroli J, He Q, et al. HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis-induced acute lung injury. Intensive Care Medicine. 2007;33(10):1829–1839. [PubMed]
106. Dvorak HF, Senger DR, Dvorak AM. Regulation of extravascular coagulation by microvascular permeability. Science. 1985;227(4690):1059–1061. [PubMed]
107. McCachren SS, Lightner VA. Expression of human tenascin in synovitis and its regulation by interleukin-1. Arthritis and Rheumatism. 1992;35(10):1185–1196. [PubMed]
108. Salter DM. Tenascin is increased in cartilage and synovium from arthritic knees. British Journal of Rheumatology. 1993;32(9):780–786. [PubMed]
109. Schett G, Redlich K, Xu Q, et al. Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue: differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. Journal of Clinical Investigation. 1998;102(2):302–311. [PMC free article] [PubMed]
110. Scott DL, Delamere JP, Walton KW. The distribution of fibronectin in the pannus in rheumatoid arthritis. British Journal of Experimental Pathology. 1981;62(4):362–368. [PubMed]
111. Taniguchi N, Kawahara K-I, Yone K, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis and Rheumatism. 2003;48(4):971–981. [PubMed]
112. Yu D, Rumore PM, Liu Q, Steinman CR. Soluble oligonucleosomal complexes in synovial fluid from inflamed joints. Arthritis and Rheumatism. 1997;40(4):648–654. [PubMed]
113. Schenk S, Muser J, Vollmer G, Chiquet-Ehrismann R. Tenascin-C in serum: a questionable tumor marker. International Journal of Cancer. 1995;61(4):443–449. [PubMed]
114. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–251. [PubMed]
115. Urbonaviciute V, Fürnrohr BG, Weber C, et al. Factors masking HMGB1 in human serum and plasma. Journal of Leukocyte Biology. 2007;81(1):67–74. [PubMed]
116. Hallgren R, Eklund A, Engstrom-Laurent A, Schmekel B. Hyaluronate in bronchoalveolar lavage fluid: a new marker in sarcoidosis reflecting pulmonary disease. British Medical Journal. 1985;290(6484):1778–1781. [PMC free article] [PubMed]
117. Milman N, Kristensen MS, Bentsen K. Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid from patients with pulmonary fibrosis. APMIS. 1995;103(10):749–754. [PubMed]
118. Riise GC, Ahlstedt S, Larsson S, et al. Bronchial inflammation in chronic bronchitis assessed by measurement of cell products in bronchial lavage fluid. Thorax. 1995;50(4):360–365. [PMC free article] [PubMed]
119. Andersson Å, Covacu R, Sunnemark D, et al. Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. Journal of Leukocyte Biology. 2008;84(5):1248–1255. [PubMed]
120. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. Journal of Leukocyte Biology. 2007;81(1):28–37. [PubMed]
121. Johnson GB, Brunn GJ, Platt JL. Cutting edge: an endogenous pathway to systemic inflammatory response syndrome (SIRS)-like reactions through Toll-Like receptor 4. Journal of Immunology. 2004;172(1):20–24. [PubMed]
122. Maher JJ. DAMPs ramp up drug toxicity. Journal of Clinical Investigation. 2009;119(2):246–249. [PMC free article] [PubMed]
123. Ishii KJ, Suzuki K, Coban C, et al. Genomic DNA released by dying cells induces the maturation of APCs. Journal of Immunology. 2001;167(5):2602–2607. [PubMed]
124. Hwang S-A, Kruzel ML, Actor JK. Lactoferrin augments BCG vaccine efficacy to generate T helper response and subsequent protection against challenge with virulent Mycobacterium tuberculosis. International Immunopharmacology. 2005;5(3):591–599. [PubMed]
125. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. Journal of Immunology. 2006;177(2):1272–1281. [PubMed]
126. Tani K, Murphy WJ, Chertov O, et al. Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens. International Immunology. 2000;12(5):691–700. [PubMed]
127. Rovere-Querini P, Capobianco A, Scaffidi P, et al. HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Reports. 2004;5(8):825–830. [PubMed]
128. Kawakami A, Osaka M, Aikawa M, et al. Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation. Circulation Research. 2008;103(12):1402–1409. [PMC free article] [PubMed]
129. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P. HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine. 2002;18(4):231–236. [PubMed]
130. Liu K, Mori S, Takahashi HK, et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB Journal. 2007;21(14):3904–3916. [PubMed]
131. O’Connor KA, Hansen MK, Pugh CR, et al. Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects. Cytokine. 2003;24(6):254–265. [PubMed]
132. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology. 2002;123(3):790–802. [PubMed]
133. Pullerits R, Jonsson I-M, Verdrengh M, et al. High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. Arthritis and Rheumatism. 2003;48(6):1693–1700. [PubMed]
134. Imaeda AB, Watanabe A, Sohail MA, et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. Journal of Clinical Investigation. 2009;119(2):305–314. [PMC free article] [PubMed]
135. Tsung A, Sahai R, Tanaka H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. Journal of Experimental Medicine. 2005;201(7):1135–1143. [PMC free article] [PubMed]
136. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. Cutting edge: HMG-1 as a mediator of acute lung inflammation. Journal of Immunology. 2000;165(6):2950–2954. [PubMed]
137. Lin X, Yang H, Sakuragi T, et al. α-chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis. American Journal of Physiology. 2005;289(4):L583–L590. [PubMed]
138. Ueno H, Matsuda T, Hashimoto S, et al. Contributions of high mobility group box protein in experimental and clinical acute lung injury. American Journal of Respiratory and Critical Care Medicine. 2004;170(12):1310–1316. [PubMed]
139. Tan MH, Sun Z, Opitz SL, Schmidt TE, Peters JH, George EL. Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. Blood. 2004;104(1):11–18. [PubMed]
140. van Zoelen MAD, Vogl T, Foell D, et al. Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. American Journal of Respiratory and Critical Care Medicine. 2009;180(11):1098–1106. [PubMed]
141. Croce K, Gao H, Wang Y, et al. Myeloid-related protein-8/14 is critical for the biological response to vascular injury. Circulation. 2009;120(5):427–436. [PMC free article] [PubMed]
142. Ziegler G, Prinz V, Albrecht MW, et al. Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia. Biochimica et Biophysica Acta. 2009;1792(12):1198–1204. [PubMed]
143. Vogl T, Tenbrock K, Ludwig S, et al. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nature Medicine. 2007;13(9):1042–1049. [PubMed]
144. Talts JF, Wirl G, Dictor M, Muller WJ, Fässler R. Tenascin-C modulates tumor stroma and monocyte/macrophage recruitment but not tumor growth or metastasis in a mouse strain with spontaneous mammary cancer. Journal of Cell Science. 1999;112(12):1855–1864. [PubMed]
145. Jiang D, Liang J, Fan J, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Medicine. 2005;11(11):1173–1179. [PubMed]
146. Liu Y-Y, Lee C-H, Dedaj R, et al. High-molecular-weight hyaluronan—a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats. Critical Care. 2008;12(4, article R102) [PMC free article] [PubMed]
147. Davé SH, Tilstra JS, Matsuoka K, et al. Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis. Journal of Leukocyte Biology. 2009;86(3):633–643. [PubMed]
148. Maeda S, Hikiba Y, Shibata W, et al. Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer. Biochemical and Biophysical Research Communications. 2007;360(2):394–400. [PubMed]
149. Ogawa EN, Ishizaka A, Tasaka S, et al. Contribution of high-mobility group box-1 to the development of ventilator-induced lung injury. American Journal of Respiratory and Critical Care Medicine. 2006;174(4):400–407. [PubMed]
150. Sawa H, Ueda T, Takeyama Y, et al. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis. World Journal of Gastroenterology. 2006;12(47):7666–7670. [PMC free article] [PubMed]
151. Yang R, Harada T, Mollen KP, et al. Anti-HMGB1 neutralizing antibody ameliorates gut barrier dysfunction and improves survival after hemorrhagic shock. Molecular Medicine. 2006;12(4–6):105–114. [PMC free article] [PubMed]
152. Kim JY, Park JS, Strassheim D, et al. HMGB1 contributes to the development of acute lung injury after hemorrhage. American Journal of Physiology. 2005;288(5):L958–L965. [PubMed]
153. Suda K, Kitagawa Y, Ozawa S, et al. Anti-high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis. World Journal of Surgery. 2006;30(9):1755–1762. [PubMed]
154. Yang H, Ochani M, Li J, et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(1):296–301. [PubMed]
155. Qin S, Wang H, Yuan R, et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. Journal of Experimental Medicine. 2006;203(7):1637–1642. [PMC free article] [PubMed]
156. Chen G, Li J, Qiang X, et al. Suppression of HMGB1 release by stearoyl lysophosphatidylcholine: an additional mechanism for its therapeutic effects in experimental sepsis. Journal of Lipid Research. 2005;46(4):623–627. [PubMed]
157. Ulloa L, Batliwalla FM, Andersson U, Gregersen PK, Tracey KJ. High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis. Arthritis and Rheumatism. 2003;48(4):876–881. [PubMed]
158. Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine. 2004;10(11):1216–1221. [PubMed]
159. Chorny A, Delgado M. Neuropeptides rescue mice from lethal sepsis by down-regulating secretion of the late-acting inflammatory mediator high mobility group box 1. American Journal of Pathology. 2008;172(5):1297–1302. [PubMed]
160. Pan P, Cardinal J, Dhupar R, et al. Low-dose cisplatin administration in murine cecal ligation and puncture prevents the systemic release of HMGB1 and attenuates lethality. Journal of Leukocyte Biology. 2009;86(3):625–632. [PubMed]
161. Andersson U, Erlandsson-Harris H. HMGB1 is a potent trigger of arthritis. Journal of Internal Medicine. 2004;255(3):344–350. [PubMed]
162. Rice JW, Veal JM, Fadden RP, et al. Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis and Rheumatism. 2008;58(12):3765–3775. [PubMed]
163. Feldman RI, Mintzer B, Zhu D, et al. Potent triazolothione inhibitor of heat-shock protein-90. Chemical Biology and Drug Design. 2009;74(1):43–50. [PubMed]
164. Hagiwara S, Iwasaka H, Togo K, Noguchi T. A neutrophil elastase inhibitor, sivelestat, reduces lung injury following endotoxin-induced shock in rats by inhibiting HMGB1. Inflammation. 2008;31(4):227–234. [PubMed]
165. Harada N, Okajima K, Isobe H. Role of neutrophil elastase in development of pulmonary vascular injury and septic shock in rats. Shock. 2008;30(4):379–387. [PubMed]
166. Morohoshi Y, Matsuoka K, Chinen H, et al. Inhibition of neutrophil elastase prevents the development of murine dextran sulfate sodium-induced colitis. Journal of Gastroenterology. 2006;41(4):318–324. [PubMed]
167. Kakimoto K, Matsukawa A, Yoshinaga M, Nakamura H. Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. Cellular Immunology. 1995;165(1):26–32. [PubMed]
168. Uchida Y, Freitas MCS, Zhao D, Busuttil RW, Kupiec-Weglinski JW. The inhibition of neutrophil elastase ameliorates mouse liver damage due to ischemia and reperfusion. Liver Transplantation. 2009;15(8):939–947. [PMC free article] [PubMed]
169. Hiratsuka S, Watanabe A, Sakurai Y, et al. The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biology. 2008;10(11):1349–1355. [PubMed]
170. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Reviews Immunology. 2005;5(4):331–342. [PubMed]
171. Mantell LL, Parrish WR, Ulloa L. Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock. 2006;25(1):4–11. [PubMed]
172. Parrish WR, Gallowitsch-Puerta M, Czura CJ, Tracey KJ. Experimental therapeutic strategies for severe sepsis: mediators and mechanisms. Annals of the New York Academy of Sciences. 2008;1144:210–236. [PubMed]
173. Voll RE, Urbonaviciute V, Fürnrohr B, Herrmann M, Kalden JR. The role of high-mobility group box 1 protein in the pathogenesis of autoimmune diseases. Current Rheumatology Reports. 2008;10(5):341–342. [PubMed]
174. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. Journal of Internal Medicine. 2004;255(3):320–331. [PubMed]
175. Pisetsky DS, Erlandsson-Harris H, Andersson U. High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease. Arthritis Research and Therapy. 2008;10(3):p. 209. [PMC free article] [PubMed]
176. Musumeci D, Roviello GN, Moccia M, et al. Bent oligonucleotide duplexes as HMGB1 inhibitors: a comparative study. Nucleosides, Nucleotides and Nucleic Acids. 2007;26(10–12):1447–1450. [PubMed]
177. Yuan Z, Chen J, Zhang Y, Peng Y. Construction and characterization of the HMGB1 mutant as a competitive antagonist to HMGB1 induced cytokines release. Biochemical and Biophysical Research Communications. 2008;372(4):703–707. [PubMed]
178. Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. Journal of Clinical Investigation. 2005;115(5):1267–1274. [PubMed]
179. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191–195. [PubMed]
180. Gardella S, Andrei C, Ferrera D, et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Reports. 2002;3(10):995–1001. [PubMed]
181. Foell D, Wittkowski H, Roth J. Mechanisms of disease: a ’DAMP’ view of inflammatory arthritis. Nature Clinical Practice Rheumatology. 2007;3(7):382–390. [PubMed]
182. Brunn GJ, Bungum MK, Johnson GB, Platt JL. Conditional signaling by Toll-like receptor 4. FASEB Journal. 2005;19(7):872–874. [PubMed]
183. Kliment CR, Tobolewski JM, Manni ML, Tan RJ, Enghild J, Oury TD. Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung. Antioxidants and Redox Signaling. 2008;10(2):261–268. [PMC free article] [PubMed]
184. Goto M, Hanyu T, Yoshio T, et al. Intra-articular injection of hyaluronate (SI-6601D) improves joint pain and synovial fluid prostaglandin E2 levels in rheumatoid arthritis: a multicenter clinical trial. Clinical and Experimental Rheumatology. 2001;19(4):377–383. [PubMed]
185. Van Eden W, Van Der Zee R, Prakken B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nature Reviews Immunology. 2005;5(4):318–330. [PubMed]
186. Hayakawa M, Katabami K, Wada T, et al. Sivelestat (selective neutrophil elastase inhibitor) improves the mortality rate of sepsis associated with both acute respiratory distress syndrome and disseminated intravascular coagulation patients. Shock. 2010;33(1):14–18. [PubMed]
187. Togo S, Matsuo K, Ishibe A, et al. Usefulness of a selective neutrophil elastase inhibitor (sivelestat) in septic ARDS patients after gastrointestinal surgery. Hepato-Gastroenterology. 2008;55(84):967–973. [PubMed]
188. Izuishi K, Tsung A, Jeyabalan G, et al. Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. Journal of Immunology. 2006;176(12):7154–7158. [PubMed]
189. Klune JR, Billiar TR, Tsung A. HMGB1 preconditioning: therapeutic application for a danger signal? Journal of Leukocyte Biology. 2008;83(3):558–563. [PubMed]
190. Zagulski T, Lipinski P, Zagulska A, Broniek S, Jarzabek Z. Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo. British Journal of Experimental Pathology. 1989;70(6):697–704. [PubMed]
191. Gariboldi S, Palazzo M, Zanobbio L, et al. Low molecular weight hyaluronic acid increases the self-defense of skin epithelium by induction of β-defensin 2 via TLR2 and TLR4. Journal of Immunology. 2008;181(3):2103–2110. [PubMed]
192. Chesler EJ, Miller DR, Branstetter LR, et al. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mammalian Genome. 2008;19(6):382–389. [PMC free article] [PubMed]
193. O’Neill LAJ. When signaling pathways collide: positive and negative regulation of Toll-like receptor signal transduction. Immunity. 2008;29(1):12–20. [PubMed]
194. Stack J, Haga IR, Schröder M, et al. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. Journal of Experimental Medicine. 2005;201(6):1007–1018. [PMC free article] [PubMed]
195. Li K, Foy E, Ferreon JC, et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(8):2992–2997. [PubMed]
196. Liu G, Friggeri A, Yang Y, Park Y-J, Tsuruta Y, Abraham E. miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15819–15824. [PubMed]
197. Liu Y, Chen G-Y, Zheng P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends in Immunology. 2009;30(12):557–561. [PMC free article] [PubMed]
198. Chen G-Y, Tang J, Zheng P, Liu Y. CD24 and siglec-10 selectively repress tissue damage—induced immune responses. Science. 2009;323(5922):1722–1725. [PMC free article] [PubMed]
199. Raby AC, Le Bouder E, Colmont C, et al. Soluble TLR2 reduces inflammation without compromising bacterial clearance by disrupting TLR2 triggering. Journal of Immunology. 2009;183(1):506–517. [PubMed]
200. Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. Journal of Immunology. 2001;167(5):2887–2894. [PubMed]
201. He RL, Zhou J, Hanson CZ, Chen J, Cheng N, Ye RD. Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2. Blood. 2009;113(2):429–437. [PubMed]
202. Sandri S, Rodriguez D, Gomes E, Monteiro HP, Russo M, Campa A. Is serum amyloid A an endogenous TLR4 agonist? Journal of Leukocyte Biology. 2008;83(5):1174–1180. [PubMed]
203. Cheng N, He R, Tian J, Ye PP, Ye RD. Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A. Journal of Immunology. 2008;181(1):22–26. [PMC free article] [PubMed]
204. Biragyn A, Ruffini PA, Leifer CA, et al. Toll-like receptor 4-dependent activation of dendritic cells by β-defensin 2. Science. 2002;298(5595):1025–1029. [PubMed]
205. Devaney JM, Greene CM, Taggart CC, Carroll TP, O’Neill SJ, McElvaney NG. Neutrophil elastase up-regulates interleukin-8 via Toll-like receptor 4. FEBS Letters. 2003;544(1–3):129–132. [PubMed]
206. Xu XH, Shah PK, Faure E, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001;104(25):3103–3108. [PubMed]
207. Bae YS, Lee JH, Choi SH, et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: Toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circulation Research. 2009;104(2):210–218. [PMC free article] [PubMed]
208. Schaeffler A, Gross P, Buettner R, et al. Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-κB pathway in adipocytes links nutritional signalling with innate immunity. Immunology. 2009;126(2):233–245. [PubMed]
209. Yang D, Chen Q, Shao BS, et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. Journal of Experimental Medicine. 2008;205(1):79–90. [PMC free article] [PubMed]
210. Little PJ, Osman N, O’Brien KD. Hyperelongated biglycan: the surreptitious initiator of atherosclerosis. Current Opinion in Lipidology. 2008;19(5):448–454. [PubMed]
211. Williams KJ. Arterial wall chondroitin sulfate proteoglycans: diverse molecules with distinct roles in lipoprotein retention and atherogenesis. Current Opinion in Lipidology. 2001;12(5):477–487. [PubMed]
212. Schaefer L, Raslik I, Grone HJ, et al. Small proteoglycans in human diabetic nephropathy: discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin. FASEB Journal. 2001;15(3):559–561. [PubMed]
213. Cs-Szabo G, Roughley PJ, Plaas AHK, Glant TT. Large and small proteoglycans of osteoarthritic and rheumatoid articular cartilage. Arthritis and Rheumatism. 1995;38(5):660–668. [PubMed]
214. Polgár A, Falus A, Koó É, et al. Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglycan and decorin in patients with rheumatoid arthritis or other joint diseases. Rheumatology. 2003;42(4):522–527. [PubMed]
215. Galamb O, Sipos F, Spisák S, et al. Potential biomarkers of colorectal adenoma-dysplasia-carcinoma progression: mRNA expression profiling and in situ protein detection on TMAs reveal 15 sequentially upregulated and 2 downregulated genes. Cellular Oncology. 2009;31(1):19–29. [PMC free article] [PubMed]
216. Nishino R, Honda M, Yamashita T, et al. Identification of novel candidate tumour marker genes for intrahepatic cholangiocarcinoma. Journal of Hepatology. 2008;49(2):207–216. [PubMed]
217. Mintz MB, Sowers R, Brown KM, et al. An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Research. 2005;65(5):1748–1754. [PubMed]
218. Weber CK, Sommer G, Michl P, et al. Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology. 2001;121(3):657–667. [PubMed]
219. Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. Journal of the American Medical Association. 2005;294(14):1799–1809. [PubMed]
220. Di Minno G, Mancini M. Measuring plasma fibrinogen to predict stroke and myocardial infarction. Arteriosclerosis. 1990;10(1):1–7. [PubMed]
221. Adams RA, Schachtrup C, Davalos D, Tsigelny I, Akassoglou K. Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis. Current Medicinal Chemistry. 2007;14(27):2925–2936. [PubMed]
222. Rybarczyk BJ, Simpson-Haidaris PJ. Fibrinogen assembly, secretion, and deposition into extracellular matrix by MCF-7 human breast carcinoma cells. Cancer Research. 2000;60(7):2033–2039. [PubMed]
223. Bidwell J, McCabe R, Rougraff B, et al. Tissue matrix protein expression in human osteoblasts, osteosarcoma tumors, and osteosarcoma cell lines. Molecular Biology Reports. 1997;24(4):271–282. [PubMed]
224. van Keulen JK, de Kleijn DP, Nijhuis MMO, et al. Levels of extra domain A containing fibronectin in human atherosclerotic plaques are associated with a stable plaque phenotype. Atherosclerosis. 2007;195(1):e83–e91. [PubMed]
225. Széll M, Bata-Csörgo Z, Koreck A, et al. Proliferating keratinocytes are putative sources of the psoriasis susceptibility-related EDA+ (extra domain A of fibronectin) oncofetal fibronectin. Journal of Investigative Dermatology. 2004;123(3):537–546. [PubMed]
226. Ting KM, Rothaupt D, McCormick TS, et al. Overexpression of the oncofetal Fn variant containing the EDA splice-in segment in the dermal-epidermal junction of psoriatic uninvolved skin. Journal of Investigative Dermatology. 2000;114(4):706–711. [PubMed]
227. Satoi S, Kitade H, Hiramatsu Y, et al. Increased extra domain-A containing fibronectin and hepatic dysfunction during septic response: an in vivo and in vitro study. Shock. 2000;13(6):492–496. [PubMed]
228. Rybak J-N, Roesli C, Kaspar M, Villa A, Neri D. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Research. 2007;67(22):10948–10957. [PubMed]
229. Villa A, Trachsel E, Kaspar M, et al. A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. International Journal of Cancer. 2008;122(11):2405–2413. [PubMed]
230. Kruse R, Merten M, Yoshida K, Schmidt A, Völker W, Buddecke E. Cholesterol-dependent changes of glycosaminoglycan pattern in human aorta. Basic Research in Cardiology. 1996;91(5):344–352. [PubMed]
231. Waterman M, Ben-Izhak O, Eliakim R, Groisman G, Vlodavsky I, Ilan N. Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Modern Pathology. 2007;20(1):8–14. [PubMed]
232. Aotsuka S, Okawa-Takatsuji M, Kinoshita M, Yokohari R. Analysis of negatively charged dye-binding antibodies reactive with double-stranded DNA and heparan sulfate in serum from patients with rheumatic diseases. Clinical and Experimental Immunology. 1988;73(3):436–442. [PubMed]
233. Cohen E, Doweck I, Naroditsky I, et al. Heparanase is overexpressed in lung cancer and correlates inversely with patient survival. Cancer. 2008;113(5):1004–1011. [PMC free article] [PubMed]
234. McKenzie EA. Heparanase: a target for drug discovery in cancer and inflammation. British Journal of Pharmacology. 2007;151(1):1–14. [PMC free article] [PubMed]
235. Porto A, Palumbo R, Pieroni M, et al. Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB Journal. 2006;20(14):2565–2566. [PubMed]
236. Devaraj S, Dasu MR, Park SH, Jialal I. Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia. 2009;52(8):1665–1668. [PMC free article] [PubMed]
237. Popovic K, Ek M, Espinosa A, et al. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis and Rheumatism. 2005;52(11):3639–3645. [PubMed]
238. Ek M, Popovic K, Harris HE, Nauclér CS, Wahren-Herlenius M. Increased extracellular levels of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with Sjögren’s syndrome. Arthritis and Rheumatism. 2006;54(7):2289–2294. [PubMed]
239. Yoshizaki A, Komura K, Iwata Y, et al. Clinical significance of serum HMGB-1 and sRAGE levels in systemic sclerosis: association with disease severity. Journal of Clinical Immunology. 2009;29(2):180–189. [PubMed]
240. Riganò R, Profumo E, Buttari B, et al. Heat shock proteins and autoimmunity in patients with carotid atherosclerosis. Annals of the New York Academy of Sciences. 2007;1107:1–10. [PubMed]
241. Van Eden W, Wick G, Albani S, Cohen I. Stress, heat shock proteins, and autoimmunity: how immune responses to heat shock proteins are to be used for the control of chronic inflammatory diseases. Annals of the New York Academy of Sciences. 2007;1113:217–237. [PubMed]
242. Peetermans WE, D’Haens GR, Ceuppens JL, Rutgeerts P, Geboes K. Mucosal expression by B7-positive cells of the 60-kilodalton heat-shock protein in inflammatory bowel disease. Gastroenterology. 1995;108(1):75–82. [PubMed]
243. Hu S, et al. The expression of molecular chaperone HSP90 and IL-6 in patients with systemic lupus erythematosus. Journal of Huazhong University of Science and Technology. Medical Sciences. 2006;26(6):664–666. [PubMed]
244. Cid C, García-Villanueva M, Salinas M, Alcázar A. Detection of anti-heat shock protein 90 β (Hsp90β) antibodies in cerebrospinal fluid. Journal of Immunological Methods. 2007;318(1-2):153–157. [PubMed]
245. Cid C, Regidor I, Poveda PD, Alcazar A. Expression of heat shock protein 90 at the cell surface in human neuroblastoma cells. Cell Stress & Chaperones. 2009;14(3):321–327. [PMC free article] [PubMed]
246. Matysiak M, Makosa B, Walczak A, Selmaj K. Patients with multiple sclerosis resisted to glucocorticoid therapy: abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex. Multiple Sclerosis. 2008;14(7):919–926. [PubMed]
247. Seung NR, Park EJ, Kim CW, et al. Comparison of expression of heat-shock protein 60, Toll-like receptors 2 and 4, and T-cell receptor γ δ in plaque and guttate psoriasis. Journal of Cutaneous Pathology. 2007;34(12):903–911. [PubMed]
248. Kee C, Cheong KY, Pham K, Waterer GW, Temple SEL. Genetic variation in heat shock protein 70 is associated with septic shock: narrowing the association to a specific haplotype. International Journal of Immunogenetics. 2008;35(6):465–473. [PubMed]
249. Messaoudi S, Peyrat JF, Brion JD, Alami M. Recent advances in Hsp90 inhibitors as antitumor agents. Anti-Cancer Agents in Medicinal Chemistry. 2008;8(7):761–782. [PubMed]
250. Luo W, Rodina A, Chiosis G. Heat shock protein 90: translation from cancer to Alzheimer’s disease treatment? BMC Neuroscience. 2008;9(supplement 3, article S7) [PMC free article] [PubMed]
251. Witter J, Roughley PJ, Webber C. The immunologic detection and characterization of cartilage proteoglycan degradation products in synovial fluids of patients with arthritis. Arthritis and Rheumatism. 1987;30(5):519–529. [PubMed]
252. Yoshizaki A, Iwata Y, Komura K, et al. Clinical significance of serum hyaluronan levels in systemic sclerosis: association with disease severity. Journal of Rheumatology. 2008;35(9):1825–1829. [PubMed]
253. Sugahara KN, Hirata T, Hayasaka H, Stern R, Murai T, Miyasaka M. Tumor cells enhance their own CD44 cleavage and motility by generating hyaluronan fragments. Journal of Biological Chemistry. 2006;281(9):5861–5868. [PubMed]
254. Henriksen PA, Sallenave J-M. Human neutrophil elastase: mediator and therapeutic target in atherosclerosis. International Journal of Biochemistry and Cell Biology. 2008;40(6-7):1095–1100. [PubMed]
255. Piwowar A, Knapik-Kordecka M, Warwas M. Concentration of leukocyte elastase in plasma and polymorphonuclear neutrophil extracts in type 2 diabetes. Clinical Chemistry and Laboratory Medicine. 2000;38(12):1257–1261. [PubMed]
256. Fischbach W, Becker W, Mossner J. Leucocyte elastase in chronic inflammatory bowel diseases: a marker of inflammatory activity? Digestion. 1987;37(2):88–95. [PubMed]
257. Bugren P, Rasmussen N, Isaksson B, Wieslander J. Anti-neutrophil cytoplasm antibodies, anti-GBM antibodies and anti-dsDNA antibodies in glomerulonephritis. European Journal of Clinical Investigation. 1992;22(12):783–792. [PubMed]
258. Figueredo CM, Areas A, Sztajnbok FR, et al. Higher elastase activity associated with lower IL-18 in GCF from juvenile systemic lupus patients. Oral Health & Preventive Dentistry. 2008;6(1):75–81. [PubMed]
259. Wong SN, Shah V, Dillon MJ. Anti-neutrophil cytoplasmic antibodies in childhood systemic lupus erythematosus. European Journal of Pediatrics. 1995;154(1):43–45. [PubMed]
260. Tsujimoto H, Ono S, Majima T, et al. Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. Shock. 2005;23(1):39–44. [PubMed]
261. Foekens JA, Ries C, Look MP, Gippner-Steppert C, Klijn JGM, Jochum M. The prognostic value of polymorphonuclear leukocyte elastase in patients with primary breast cancer. Cancer Research. 2003;63(2):337–341. [PubMed]
262. Shimada S, Yamaguchi K, Takahashi M, Ogawa M. Pancreatic elastase IIIA and its variants are expressed in pancreatic carcinoma cells. International Journal of Molecular Medicine. 2002;10(5):599–603. [PubMed]
263. Taniguchi K, Yang P, Jett J, et al. Polymorphisms in the promoter region of the neutrophil elastase gene are associated with lung cancer development. Clinical Cancer Research. 2002;8(4):1115–1120. [PubMed]
264. McCormick MM, Rahimi F, Bobryshev YV, et al. S100A8 and S100A9 in human arterial wall: implications for atherogenesis. Journal of Biological Chemistry. 2005;280(50):41521–41529. [PubMed]
265. Lugering N, Stoll R, Kucharzik T, et al. Immunohistochemical distribution and serum levels of the Ca2+-binding proteins MRP8, MRP14 and their heterodimeric form MRP8/14 in Crohn’s disease. Digestion. 1995;56(5):406–414. [PubMed]
266. Lugering N, Stoll R, Schmid KW, et al. The myeloic related protein MRP8/14 (27E10 antigen)—usefulness as a potential marker for disease activity in ulcerative colitis and putative biological function. European Journal of Clinical Investigation. 1995;25(9):659–664. [PubMed]
267. Haga H-J, Brun JG, Berntzen HB, Cervera R, Khamashta M, Hughes GRV. Calprotection in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity. Lupus. 1993;2(1):47–50. [PubMed]
268. Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature. 2005;437(7057):369–375. [PubMed]
269. Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis and Rheumatism. 2004;50(12):3762–3771. [PubMed]
270. Odink K, Cerletti N, Bruggen J, et al. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature. 1987;330(6143):80–82. [PubMed]
271. Youssef P, Roth J, Frosch M, et al. Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. Journal of Rheumatology. 1999;26(12):2523–2528. [PubMed]
272. Wallner K, Li C, Shah PK, et al. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation. 1999;99(10):1284–1289. [PubMed]
273. Amin K, Lúdvíksdóttir D, Janson C, et al. Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group. American Journal of Respiratory and Critical Care Medicine. 2000;162(6):2295–2301. [PubMed]
274. Karjalainen E-M, Lindqvist A, Laitinen LA, et al. Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma. Respiratory Medicine. 2003;97(9):1045–1051. [PubMed]
275. Ljubimov AV, Burgeson RE, Butkowski RJ, et al. Basement membrane abnormalities in human eyes with diabetic retinopathy. Journal of Histochemistry and Cytochemistry. 1996;44(12):1469–1479. [PubMed]
276. Loots MAM, Lamme EN, Zeegelaar J, Mekkes JR, Bos JD, Middelkoop E. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. Journal of Investigative Dermatology. 1998;111(5):850–857. [PubMed]
277. Riedl S, Tandara A, Reinshagen M, et al. Serum tenascin-C is an indicator of inflammatory bowel disease activity. International Journal of Colorectal Disease. 2001;16(5):285–291. [PubMed]
278. Kaarteenaho-Wiik R, Lakari E, Soini Y, Pollanen R, Kinnula VL, Paakko P. Tenascin expression and distribution in pleural inflammatory and fibrotic diseases. Journal of Histochemistry and Cytochemistry. 2000;48(9):1257–1268. [PubMed]
279. Paallysaho T, Tervo K, Kivela T, Virtanen I, Tarkkanen A, Tervo T. Cellular fibronectin and tenascin in an orbital nylon prosthesis removed because of infection caused by Staphylococcus aureus. Graefe’s Archive for Clinical and Experimental Ophthalmology. 1993;231(2):61–65. [PubMed]
280. Gutowski NJ, Newcombe J, Cuzner ML. Tenascin-R and C in multiple sclerosis lesions: relevance to extracellular matrix remodelling. Neuropathology and Applied Neurobiology. 1999;25(3):207–214. [PubMed]
281. Chevalier X, Groult N, Larget-Piet B, Zardi L, Hornebeck W. Tenascin distribution in articular cartilage from normal subjects and from patients with osteoarthritis and rheumatoid arthritis. Arthritis and Rheumatism. 1994;37(7):1013–1022. [PubMed]
282. Hasegawa M, Nakoshi Y, Muraki M, et al. Expression of large tenascin-C splice variants in synovial fluid of patients with rheumatoid arthritis. Journal of Orthopaedic Research. 2007;25(5):563–568. [PubMed]
283. Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Letters. 2006;244(2):143–163. [PubMed]
284. Sobel RA, Ahmed AS. White matter extracellular matrix chondroitin sulfate/dermatan sulfate proteoglycans in multiple sclerosis. Journal of Neuropathology and Experimental Neurology. 2001;60(12):1198–1207. [PubMed]
285. Ricciardelli C, Sakko AJ, Ween MP, Russell DL, Horsfall DJ. The biological role and regulation of versican levels in cancer. Cancer and Metastasis Reviews. 2009;28(1-2):233–245. [PubMed]

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