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1.  A novel TLR2-triggered signalling crosstalk synergistically intensifies TNF-mediated IL-6 induction 
Toll-like receptors (TLR) recognize pathogens and trigger the production of vigorous pro-inflammatory cytokines [such as tumour necrosis factor (TNF)] that induce systemic damages associated with sepsis and chronic inflammation. Cooperation between signals of TLR and TNF receptor has been demonstrated through the participation of TNF receptor 1 (TNFR) adaptors in endotoxin tolerance. Here, we identify a TLR2-mediated synergy, through a MyD88-independent crosstalk, which enhances subsequent TNF-mediated nuclear factor-kappa B activation and interleukin-6 induction. Membrane-associated adaptor MAL conduces the link between TNF receptor-associated factor 6 (TRAF6) and TNFR-associated death domain, leading to a distinctive K63-ubiquitinylated TRAF6 recruitment into TNFR complex. In summary, our results reveal a novel route of TLR signal that synergistically amplifies TNF-mediated responses, indicating an innovative target for inflammation manipulation.
doi:10.1111/jcmm.12294
PMCID: PMC4124019  PMID: 24758719
Toll-like receptor; tumour necrosis factor; signalling crosstalk; TRAF6; TRADD
2.  A Potential Role of Myeloid DAP12-Associating Lectin (MDL)-1 in the Regulation of Inflammation in Rheumatoid Arthritis Patients 
PLoS ONE  2014;9(1):e86105.
The pathogenic roles of myeloid DAP12-associating lectin-1(MDL-1) and DAP12 in human rheumatoid arthritis (RA) remain unknown. Frequencies of MDL-1-expressing monocytes in 22 active RA patients, 16 inactive RA patients, 12 osteoarthritis (OA) patients and 10 healthy controls (HC) were determined by flow-cytometry analysis. The mRNA expression levels of MDL-1 and DAP12 on PBMCs were evaluated by quantitative PCR, and their protein expression levels in the synovium were examined by immunohistochemistry. Significantly higher median percentages of circulating MDL-1-expressing monocytes were observed in active RA patients (53.6%) compared to inactive RA patients (34.1%), OA patients (27.9%), and HC (21.2%). Levels of MDL-1 and DAP12 gene expression in PBMCs and their protein expression in the synovium were significantly higher in active RA patients than in inactive RA or OA patients. MDL-1 levels were positively correlated with parameters of disease activity, articular damage, and levels of proinflammatory cytokines. MDL-1 activator (Dengue virus type 2 antigen) stimulation on PBMCs resulted in significantly enhanced levels of proinflammatory cytokines in RA patients compared to those in OA patients or HC, indicating that MDL-1 activation is functional. Frequencies of MDL-1-expressing monocytes and levels of MDL-1 and DAP12 gene expression significantly decreased after effective therapy. Concordant overexpression of MDL-1 and DAP12 were correlated with increased production of proinflammatory cytokines in RA patients, suggesting their roles in regulating articular inflammation.
doi:10.1371/journal.pone.0086105
PMCID: PMC3897620  PMID: 24465901
3.  Distinct regulation of dengue virus-induced inflammasome activation in human macrophage subsets 
Macrophages (Mϕ) are the major source of inflammatory cytokines and are target cells for dengue virus (DV) replication. However, Mϕ are heterogeneous and their phenotypic and functional diversities are influenced by cytokines that regulate their differentiation, tissue distribution, and defense against invading pathogens. In vitro, human primary macrophages are derived from peripheral blood CD14+ monocytes in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF). These are essential for developing tissue/resting macrophages (M-Mϕ) and inflammatory macrophages (GM-Mϕ), respectively. While IFN production is similar between M-Mϕ and GM-Mϕ, M-Mϕ cannot produce IL-1β after DV infection. In contrast, GM-Mϕ is more susceptible to DV infection and DV triggers CLEC5A in GM-Mϕ to activate NLRP3 inflammasomes, which in turn release IL-18 and IL-1β that are critical for Th17 activation and contribute to disease severity. Thus, GM-Mϕ is more representative than M-Mϕ for investigating inflammasome activation in dengue infection, and is invaluable for revealing the molecular mechanism of pathogen-induced inflammatory reaction. Distinct phenotypes of macrophage subsets under the influence of M-CSF and GM-CSF raise the question of optimal conditions for culturing primary macrophages to study host-pathogen interaction.
doi:10.1186/1423-0127-20-36
PMCID: PMC3686598  PMID: 23742038
Dengue Virus (DV); Inflammasomes; Macrophages (Mϕ); Resting macrophages (M- Mϕ); Inflammatory macrophages (GM- Mϕ); C-type lectin receptor (CLR); CLEC5A
4.  CLEC4F Is an Inducible C-Type Lectin in F4/80-Positive Cells and Is Involved in Alpha-Galactosylceramide Presentation in Liver 
PLoS ONE  2013;8(6):e65070.
CLEC4F, a member of C-type lectin, was first purified from rat liver extract with high binding affinity to fucose, galactose (Gal), N-acetylgalactosamine (GalNAc), and un-sialylated glucosphingolipids with GalNAc or Gal terminus. However, the biological functions of CLEC4F have not been elucidated. To address this question, we examined the expression and distribution of murine CLEC4F, determined its binding specificity by glycan array, and investigated its function using CLEC4F knockout (Clec4f−/−) mice. We found that CLEC4F is a heavily glycosylated membrane protein co-expressed with F4/80 on Kupffer cells. In contrast to F4/80, CLEC4F is detectable in fetal livers at embryonic day 11.5 (E11.5) but not in yolk sac, suggesting the expression of CLEC4F is induced as cells migrate from yolk cells to the liver. Even though CLEC4F is not detectable in tissues outside liver, both residential Kupffer cells and infiltrating mononuclear cells surrounding liver abscesses are CLEC4F-positive upon Listeria monocytogenes (L. monocytogenes) infection. While CLEC4F has strong binding to Gal and GalNAc, terminal fucosylation inhibits CLEC4F recognition to several glycans such as Fucosyl GM1, Globo H, Bb3∼4 and other fucosyl-glycans. Moreover, CLEC4F interacts with alpha-galactosylceramide (α-GalCer) in a calcium-dependent manner and participates in the presentation of α-GalCer to natural killer T (NKT) cells. This suggests that CLEC4F is a C-type lectin with diverse binding specificity expressed on residential Kupffer cells and infiltrating monocytes in the liver, and may play an important role to modulate glycolipids presentation on Kupffer cells.
doi:10.1371/journal.pone.0065070
PMCID: PMC3675125  PMID: 23762286
5.  Apoptosis-associated biomarkers in tuberculosis: promising for diagnosis and prognosis prediction 
Background
Apoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication.
Methods
Patients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed.
Results
One hundred TB patients and 92 IGRA-negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival.
Conclusion
Apoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation.
doi:10.1186/1471-2334-13-45
PMCID: PMC3566962  PMID: 23356448
Apoptosis; Decoy receptor 3; Latent tuberculosis infection; Lipoxin; Prostaglandin E2; Tuberculosis
6.  CLEC5A Regulates Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality 
PLoS Pathogens  2012;8(4):e1002655.
CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1−/− mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A-deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a−/− macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1−/−) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV-induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus-induced brain damage.
Author Summary
Japanese encephalitis (JE) is one of the most common forms of viral encephalitis worldwide, and the common complication post viral encephalitis is permanent neuropsychiatric sequelae resulting from severe neuroinflammation. However, specific treatment to inhibit JEV-induced neuroinflammation is not available. We found that JEV interacts directly with CLEC5A, a C-type lectin expressed on the myeloid cell surface. This observation led to two major findings; first, we demonstrate that JEV activates macrophages and microglia via CLEC5A, and blockade of CLEC5A reduces bystander neuronal damage and JEV-induced proinflammatory cytokine secretion from macrophages and microglia. Second, peripheral administration of anti-CLEC5A mAb does not only inhibit JEV-induced BBB permeability, but also reduces the numbers of activated microglia and cell infiltration into the CNS. The attenuation of neuronal damage and reduced viral load correlate with the suppression of inflammatory cytokines TNF-α, IL-6, IL-18, and MCP-1 in the CNS. Our studies provide new insights into the molecular mechanism of neuroinflammation, and reveal a possible strategy to control neuroinflammation during viral encephalitis.
doi:10.1371/journal.ppat.1002655
PMCID: PMC3334897  PMID: 22536153
7.  Survey of immune-related, mannose/fucose-binding C-type lectin receptors reveals widely divergent sugar-binding specificities 
Glycobiology  2010;21(4):512-520.
C-type lectins (CTLs) are proteins that contain one or more carbohydrate-recognition domains (CRDs) that require calcium for sugar binding and share high degree of sequence homology and tertiary structure. CTLs whose CRD contain EPN (Glu-Pro-Asn) tripeptide motifs have potential to bind mannose (Man), N-acetylglucosamine (GlcNAc), glucose (Glc) and l-fucose (Fuc), whereas those with QPD (Glu-Pro-Asp) tripeptide motifs bind galactose (Gal) and N-acetylgalactosamine (GalNAc). We report here for the first time a direct comparison of monosaccharide (and some di- and trisaccharides)-binding characteristics of 11 EPX-containing (X = N, S or D) immune-related CTLs using a competition assay and an enzyme-linked immunosorbent assay, and neoglycoproteins as ligand. The EPX CTLs studied are DC-SIGN, L-SIGN, mSIGNR1, human and mouse mannose receptors, Langerin, BDCA-2, DCIR, dectin-2, MCL and MINCLE. We found that: (1) they all bound Man and Fuc; (2) binding of Glc and GlcNAc varied considerably among these lectins, but was always less than Man and Fuc; (3) in general, Gal and GalNAc were not bound. However, dectin-2, DCIR and MINCLE showed ability to bind Gal/GalNAc; (4) DC-SIGN, L-SIGN, mSIGNR1 and Langerin showed enhanced binding of Manα2Man over Man, whereas all others showed no enhancement; (5) DC-SIGN bound Lex trisaccharide structure, which has terminal Gal and Fuc residues, more avidly than Fuc, whereas L-SIGN, mSIGNR1, DCIR and MINCLE bound Lex less avidly than Fuc. BDCA-2, dectin-2, Langerin, MCL and mannose receptor did not bind Lex at all.
doi:10.1093/glycob/cwq193
PMCID: PMC3055596  PMID: 21112966
C-type lectin; mannose/fucose-binding; immune receptor; binding specificity
8.  Vaccination targeting surface FomA of Fusobacterium nucleatum against bacterial co-aggregation: implication for treatment of periodontal infection and halitosis 
Vaccine  2010;28(19):3496-3505.
The mechanical therapy with multiple doses of antibiotics is one of modalities for treatment of periodontal diseases. However, treatments using multiple doses of antibiotics carry risks of generating resistant strains and misbalancing the resident body flora. We present an approach via immunization targeting an outer membrane protein FomA of Fusobacterium nucleatum, a central bridging organism in the architecture of oral biofilms. Neutralization of FomA considerably abrogated the enhancement of bacterial co-aggregation, biofilms and production of volatile sulfur compounds mediated by an interspecies interaction of F. nucleatum with Porphyromonas gingivalis (P. gingivalis). Vaccination targeting FomA also conferred a protective effect against co-infection-induced gum inflammation. Here, we advance a novel infectious mechanism by which F. nucleatum co-opts P. gingivalis to exacerbate gum infections. FomA is highlighted as a potential target for development of new therapeutics against periodontal infection and halitosis in humans.
doi:10.1016/j.vaccine.2010.02.047
PMCID: PMC2855893  PMID: 20189489
Co-aggregation; Fusobacterium nucleatum; FomA; Porphyromonas gingivalis; Vaccine; Abscesses; Halitosis
9.  Inhibitory Effects of Ethyl Acetate Extract of Andrographis paniculata on NF-κB Trans-Activation Activity and LPS-Induced Acute Inflammation in Mice 
This study was to investigate anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (AP). The effects of ethyl acetate (EtOAc) extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-κB) driven luciferase assay. The results showed that AP significantly inhibited NF-κB luciferase activity and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), macrophage inflammatory protein-2 (MIP-2) and nitric oxide (NO) secretions from lipopolysaccharide (LPS)/interferon-γ stimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of AP in vivo, BALB/c mice were tube-fed with 0.78 (AP1), 1.56 (AP2), 3.12 (AP3) and 6.25 (AP4) mg kg−1 body weight (BW)/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent) groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg−1 BW PDTC and 1 h later, all of the mice were injected with 15 mg kg−1 BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated for in vivo parameters. The results showed that the AP and PDTC groups had significantly lower TNF-α, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.
doi:10.1093/ecam/nep120
PMCID: PMC3096457  PMID: 19745004
10.  Humoral Immunity against Capsule Polysaccharide Protects the Host from magA+ Klebsiella pneumoniae-Induced Lethal Disease by Evading Toll-Like Receptor 4 Signaling ▿  
Infection and Immunity  2008;77(2):615-621.
Klebsiella pneumoniae magA (for mucoviscosity-associated gene A) is linked to the pathogenesis of primary pyogenic liver abscess, but the underlying mechanism by which magA increases pathogenicity is not well elucidated. In this study, we investigated the role of the capsular polysaccharides (CPS) in the pathogenesis of magA+ K. pneumoniae by comparing host immunity to magA+ K. pneumoniae and a ΔmagA mutant. We found that Toll-like receptor 4 recognition by magA+ K. pneumoniae was hampered by the mucoviscosity of the magA+ K. pneumoniae CPS. Interestingly, monoclonal antibodies (MAbs) against magA+ K. pneumoniae CPS recognized all of the K1 strains tested but not the ΔmagA and non-K1 strains. Moreover, the anti-CPS MAbs protected mice from magA+ K. pneumoniae-induced liver abscess formation and lethality. This indicates that the K1 epitope is a promising target for vaccine development, and anti-CPS MAbs has great potential to protect host from K1 strain-induced mortality and morbidity in diabetic and other immunocompromised patients in the future.
doi:10.1128/IAI.00931-08
PMCID: PMC2632026  PMID: 19015249
11.  Epstein-Barr Virus Transcription Activator Rta Upregulates Decoy Receptor 3 Expression by Binding to Its Promoter▿  
Journal of Virology  2007;81(9):4837-4847.
Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor superfamily that is overexpressed in various malignant tumor types. DcR3 has been implicated in tumor cell survival by inhibiting apoptosis and by interfering with immune surveillance. A previous study showed that DcR3 expression is associated with Epstein-Barr virus (EBV)-positive lymphomas but rarely with non-EBV-positive B-cell lymphomas, suggesting that the presence of EBV may affect DcR3 expression. Here, we demonstrated enhanced DcR3 expression upon EBV reactivation in P3HR1 cells and in EBV-infected 293 cells. This enhancement, however, could not be detected in 293 cells infected with EBV with BRLF1 deleted. We found that EBV transactivator, Rta, could upregulate DcR3 expression by direct binding to an Rta-responsive element (RRE) located in the DcR3 promoter region and that this RRE is important for Rta-mediated DcR3 expression. Overexpressing CREB-binding protein (CBP) further enhanced Rta-dependent DcR3 expression, suggesting Rta-dependent DcR3 transcription activity is mediated by CBP. Previously, Rta was shown to enhance phosphatidylinositol-3 kinase (PI3-K) activity. However, Rta-transduced PI 3-K activity plays a minor role in DcR3 expression. This is the first report to demonstrate that Rta upregulates a cellular gene by direct binding to an RRE.
doi:10.1128/JVI.02448-06
PMCID: PMC1900157  PMID: 17301127
12.  Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice 
The Journal of Experimental Medicine  2004;199(8):1143-1151.
Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic β cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in β cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.
doi:10.1084/jem.20031939
PMCID: PMC2211895  PMID: 15078896
NOD; Fas ligand; LIGHT; T helper 1 cell; T regulatory cell

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