TLR2 and TLR5 ligation directly induces β2-integrin activation, promoting cell adhesion to ICAM-1. Systemic in vivo administration of the TLR2 ligand Pam3CSK4 increases integrin-dependent adhesion to endothelium within minutes. The signaling pathway linking TLR ligation with β2-integin activation involves Rac-1, NADPH oxidase 2, and Rap1-GTPase.
Rapid β2-integrin activation is indispensable for leukocyte adhesion and recruitment to sites of infection and is mediated by chemokine- or P-selectin glycoprotein ligand-1–induced inside-out signaling. Here we uncovered a novel pathway for rapid activation of integrin-dependent leukocyte adhesion, triggered by toll-like receptor (TLR)–mediated signaling. TLR2 or TLR5 ligation rapidly activated integrin-dependent leukocyte adhesion to immobilized ICAM-1 and fibronectin. Consistently, in vivo administration of the TLR2-ligand Pam3CSK4 increased integrin-dependent slow rolling and adhesion to endothelium within minutes, as identified by intravital microscopy in the cremaster model. TLR2 and TLR5 ligation increased β2-integrin affinity, as assessed by the detection of activation-dependent neoepitopes. TLR2- and TLR5-triggered integrin activation in leukocytes required enhanced Rap1 GTPase activity, which was mediated by Rac1 activation and NADPH oxidase-2–dependent reactive oxygen species production. This novel direct pathway linking initial pathogen recognition by TLRs to rapid β2-integrin activation may critically regulate acute leukocyte infiltration to sites of pathogen invasion.
Obese adipose tissue (AT)3 inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, as compared to lean AT. Additionally, C5a was present in obese AT in the proximity of macrophage-rich crown-like structures. C5aR-sufficient and –deficient mice were fed a high fat diet (HFD) or a normal diet (ND). C5aR-deficiency was associated with increased AT weight upon ND in males but not in females and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR−/− mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR−/− mice was associated with reduced accumulation of total and pro-inflammatory M1 macrophages in the obese AT, increased expression of IL-10 and decreased AT fibrosis. In contrast no difference in beta cell mass was observed due to C5aR-deficiency under HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.
obesity; inflammation; insulin resistance; diabetes; complement
Leukocyte adhesion deficiency Type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of β2 integrins. LAD-I is invariably associated with severe periodontal bone loss, historically attributed to lack of neutrophil surveillance of the periodontal infection. Here, we challenge this dogma by showing that the cytokine IL-17 plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients, or in LFA-1 (CD11a/CD18)-deficient mice that exhibit the LAD-I periodontal phenotype, was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue. The pathological elevation of IL-17 in the LFA-1–deficient periodontal tissue derived also from innate lymphoid cells. Strikingly, local treatment with anti-IL-17 (or anti-IL-23) in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Our findings therefore support an IL-17-targeted therapy for this condition.
Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi-functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders.
Complement; Insulin resistance; Pancreas; Diabetes; Adipose tissue; Liver; Steatosis
Leukocyte recruitment is a central immune process. Multiple factors have been described to promote leukocyte infiltration into inflamed tissues, but only recently has evidence for endogenous negative modulators of this inflammatory process emerged. The discovery of several locally produced modulators has emerged into a new field of endogenous inhibitors of leukocyte extravasation. Recent findings from several inflammatory disease models show that tissues can self-regulate the recruitment of inflammatory cells, suggesting that local tissues may have a greater “regulatory say” over the immune response than previously appreciated. Here, we propose that locally produced modulators of leukocyte recruitment may represent local homeostatic mechanisms that tissues and organs may have evolved for protection against the destructive potential of the immune system.
Developmental endothelial locus-1 (Del-1) is an endothelial cell-secreted protein that limits the recruitment of neutrophils by antagonizing the interaction between the LFA-1 integrin on neutrophils and the intercellular adhesion molecule (ICAM)-1 on endothelial cells. Mice with genetic or age-associated Del-1 deficiency exhibit increased neutrophil infiltration in the periodontium resulting in inflammatory bone loss. Here we investigated additional novel mechanisms whereby Del-1 could interfere with neutrophil recruitment and inflammation. Treatment of human endothelial cells with Del-1 did not affect the expression of endothelial molecules involved in the leukocyte adhesion cascade (ICAM-1, VCAM-1, and E-selectin). Moreover, genetic or age-associated Del-1 deficiency did not significantly alter the expression of these adhesion molecules in the murine periodontium, further ruling out altered adhesion molecule expression as a mechanism whereby Del-1 regulates leukocyte recruitment. Strikingly, Del-1 inhibited ICAM-1-dependent chemokine release (CXCL2, CCL3) by neutrophils. Therefore, Del-1 could potentially suppress the amplification of inflammatory cell recruitment mediated through chemokine release by infiltrating neutrophils. Interestingly, Del-1 was itself regulated by inflammatory stimuli, which generally exerted opposite effects on adhesion molecule expression. The reciprocal regulation between Del-1 and inflammation may contribute to optimally balance the protective and the potentially harmful effects of inflammatory cell recruitment.
Junctional adhesion molecule C (JAM-C) is a transmembrane protein with significant roles in regulation of endothelial cell (EC) functions, including immune cell recruitment and angiogenesis. As these responses are important in promoting tumor growth, the role of EC JAM-C in tumor development was investigated using the ID8 syngeneic model of ovarian cancer. Within 10–15 wk, intraperitoneally injected ID8 cells form multiple tumor deposits and ascites that resemble human high-grade serous ovarian cancer. Compared to wild-type mice, survival in this model was increased in EC JAM-C knockouts (KOs; 88 vs. 96 d, P=0.04) and reduced in EC JAM-C transgenics (88 vs. 78.5 d, P=0.03), mice deficient in or overexpressing EC JAM-C, respectively. While tumor growth was significantly reduced in EC JAM-C KOs (87% inhibition at 10 wk, P<0.0005), this was not associated with alterations in tumor vessel density or immune cell infiltration. However, tumor microvessels from EC JAM-C-deficient mice exhibited reduced pericyte coverage and increased vascular leakage, suggesting a role for EC JAM-C in the development of functional tumor vessels. These findings provide evidence for a role for EC JAM-C in tumor growth and aggressiveness as well as recruitment of pericytes to newly formed blood vessels in a model of ovarian cancer.—Leinster, D. A., Colom, B., Whiteford, J. R., Ennis, D. P., Lockley, M., McNeish, I. A., Aurrand-Lions, M., Chavakis, T., Imhof, B. A., Balkwill, F. R., Nourshargh, S. Endothelial cell junctional adhesion molecule C plays a key role in the development of tumors in a murine model of ovarian cancer.
pericytes; angiogenesis; vascular development; immune cell infiltrate
Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined.
Here we addressed the role of platelets in mediating CNS inflammation in EAE.
We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control non-diseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression upon platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ib alpha (GPIbα) promotes both platelet adhesion as well as inflammatory actions of platelets, and, targeting of GPIbα attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa) also reduced EAE severity in mice.
Thus, platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.
Platelets; EAE; inflammation; autoimmune disease
Junctional adhesion molecule-C (JAM-C) is an adhesion molecule expressed at junctions between adjacent endothelial and epithelial cells and implicated in multiple inflammatory and vascular responses. In addition, we recently reported on the expression of JAM-C in Schwann cells (SCs) and its importance for the integrity and function of peripheral nerves. To investigate the role of JAM-C in neuronal functions further, mice with a specific deletion of JAM-C in SCs (JAM-C SC KO) were generated. Compared to wild-type (WT) controls, JAM-C SC KO mice showed electrophysiological defects, muscular weakness, and hypersensitivity to mechanical stimuli. In addressing the underlying cause of these defects, nerves from JAM-C SC KO mice were found to have morphological defects in the paranodal region, exhibiting increased nodal length as compared to WTs. The study also reports on previously undetected expressions of JAM-C, namely on perineural cells, and in line with nociception defects of the JAM-C SC KO animals, on finely myelinated sensory nerve fibers. Collectively, the generation and characterization of JAM-C SC KO mice has provided unequivocal evidence for the involvement of SC JAM-C in the fine organization of peripheral nerves and in modulating multiple neuronal responses.—Colom, B., Poitelon, Y., Huang, W., Woodfin, A., Averill, S., Del Carro, U., Zambroni, D., Brain, S. D., Perretti, M., Ahluwalia, A., Priestley, J. V., Chavakis, T., Imhof, B. A., Feltri, M. L., Nourshargh, S. Schwann cell-specific JAM-C-deficient mice reveal novel expression and functions for JAM-C in peripheral nerves.
adhesion molecules; tight junctions; peripheral nerves
Aging is linked to increased susceptibility to chronic inflammatory diseases several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here, we found that aging-associated periodontitis was accompanied by diminished expression of Del-1 (EDIL3), an endogenous inhibitor of LFA-1 integrin-dependent neutrophil adhesion, and by a reciprocal increase in IL-17 expression. Consistently, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent neutrophil recruitment. Young Del-1-deficient mice developed spontaneous periodontitis featuring excessive neutrophil infiltration and IL-17 expression; disease was prevented in Del-1–LFA-1 and Del-1–IL-17 receptor double-deficient mice. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation, and bone loss. Therefore, Del-1 suppresses LFA-1-dependent neutrophil recruitment and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic for inflammatory diseases.
MFG-E8 (lactadherin, SED1) is a secreted glycoprotein that has been previously implicated in enhancement of VEGF-dependent angiogenesis. Major sources of MFG-E8 in vivo, and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo, and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis.
Methods and Results
We utilized knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor β (PDGFRβ)+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor- and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering (si)RNAs and short hairpin (sh)RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathologic angiogenesis in vivo.
These studies strongly implicate MFG-E8 in pericytes/pericyte precursor function, and indicate that MFG-E8-directed therapeutics may merit further development.
MFG-E8; pericyte; angiogenesis; oxygen-induced retinopathy; melanoma
JAM-C blockade may be useful for CNV suppression by inhibiting macrophage transmigration, RPE cell migration, and monolayer RPE barrier malfunction. These data reveal a novel function of JAM-C and demonstrate that JAM-C may be a compelling target for CNV therapy.
To identify the expression of junctional adhesion molecule-C (JAM-C) in choroidal neovascularization (CNV) and evaluate the effect of JAM-C targeting on CNV formation and on cellular functions relevant to CNV in vitro, such as macrophage transmigration, human retinal pigment epithelial (hRPE) cell migration, and monolayer RPE permeability.
JAM-C expression in CNV was analyzed by real-time PCR, immunoblot analysis, and immunofluorescence staining. CNV area and blood vessel leakage were quantified using isolectin B4 staining and fluorescein angiography, respectively, 1 week after laser treatment. Macrophage infiltration within the CNV area was measured by immunofluorescence, and transmigration through monolayer RPE was analyzed using a transepithelial migration assay. After JAM-C shRNA transfection, human RPE cell migration was quantified using a transwell assay, and monolayer RPE permeability was determined by measuring the apical-to-basolateral movements of sodium fluorescein.
JAM-C expression was upregulated during CNV formation after laser treatment in a time-dependent manner. However, no change in JAM-C expression was found in the retina up to 14 days after laser treatment. JAM-C targeting by intravitreal injection of JAM-C Fc chimera inhibited CNV, blood vessel leakage, and macrophage infiltration. JAM-C Fc chimera inhibited basolateral-to-apical transmigration in vitro through a monolayer of hRPE of macrophages from patients with wet AMD. In addition, shRNA-mediated JAM-C knockdown inhibited hRPE cell migration and hRPE permeability.
JAM-C blockade may prove useful for CNV suppression by inhibiting macrophage transmigration, RPE cell migration, and monolayer RPE barrier malfunction.
Hematogenous dissemination of melanoma is a life-threatening complication of this malignant tumor. Here, we identified Junctional Adhesion Molecule-C (JAM-C) as a novel player in melanoma metastasis to the lung. JAM-C expression was identified in human and murine melanoma cell lines, in human malignant melanoma, as well as in metastatic melanoma including melanoma lung metastasis. JAM-C expressed on both murine B16 melanoma cells as well as on endothelial cells, promoted the transendothelial migration of the melanoma cells. We generated mice with inactivation of JAM-C. JAM-C−/− mice as well as endothelial-specific JAM-C-deficient mice displayed significantly decreased B16 melanoma cell metastasis to the lung, whereas treatment of mice with soluble JAM-C prevented melanoma lung metastasis. Together, JAM-C represents a novel therapeutic target for melanoma metastasis.
Neutrophil migration into inflamed tissues is a fundamental component of innate immunity. A decisive step in this process is the polarised migration of blood neutrophils through endothelial cells (ECs) lining the venular lumen (transendothelial cell migration; TEM) in a luminal to abluminal direction. Using real-time confocal imaging we report that neutrophils can exhibit disrupted polarised TEM (“hesitant” and “reverse”) in vivo. These events were noted in inflammation following ischemia-reperfusion injury, characterised by reduced expression of junctional adhesion molecule C (JAM-C) from EC junctions, and were enhanced by EC JAM-C blockade or genetic deletion. The results identify JAM-C as a key regulator of polarised neutrophil TEM in vivo and suggest that reverse TEM neutrophils can contribute to dissemination of systemic inflammation.
Neovascularisation is critical in several malignant and inflammatory conditions, as well as in the course of eye disorders. During new vessel formation, endothelial cell functions, such as proliferation and sprouting are very important and are regulated by a variety of growth factors. The DNA damage response machinery as well as factors regulating histone modifications, such as histone deacetylases, regulate cell fate as well as gene expression. Recent evidence has pointed to potential interactions among BRCA1, H2AX and SIRT1 in these intracellular pathways and neovascularisation, which will be reviewed here.
γ-H2AX; BRCA1; Sirtuins; Angiogenesis
Postnatal neovascularization is triggered by tissue hypoxia and the hypoxia-inducible transcription factor dependent upregulation of vascular growth factors. At the same time hypoxia is associated with replication stress and can induce a cellular DNA repair response including the phosphorylation of histone H2AX. Recent findings point to a role of H2AX in endothelial cell proliferation under hypoxia and thereby in hypoxia-driven neovascularization.
Leukocyte recruitment plays a major role in the immune response to infectious pathogens and during inflammatory and autoimmune disorders. The process of leukocyte extravasation from the blood into the inflamed tissue requires a complex cascade of adhesive events between the leukocytes and the endothelium including leukocyte rolling, adhesion and transendothelial migration. Leukocyte-endothelial interactions are mediated by tightly regulated binding interactions between adhesion receptors on both cells. In this regard, leukocyte adhesion onto the endothelium is governed by leukocyte integrins and their endothelial counter-receptors of the immunoglobulin superfamily. The present review will focus on novel aspects with respect to the modulation of the leukocyte adhesion cascade.
At sites of inflammation, infection or vascular injury local proinflammatory or pathogen-derived stimuli render the luminal vascular endothelial surface attractive for leukocytes. This innate immunity response consists of a well defined and regulated multistep cascade involving consecutive steps of adhesive interactions between the leukocytes and the endothelium. During the initial contact with the activated endothelium leukocytes roll along the endothelium via a loose bond which is mediated by selectins. Subsequently leukocytes are activated by chemokines presented on the luminal endothelial surface, which results in the activation of leukocyte integrins and the firm leukocyte arrest on the endothelium. After their firm adhesion, leukocytes make use of two transmigration processes to pass the endothelial barrier, the transcellular route through the endothelial cell body or the paracellular route through the endothelial junctions. In addition, further circulating cells, such as platelets arrive early at sites of inflammation contributing to both coagulation and to the immune response in parts by facilitating leukocyte-endothelial interactions. Platelets have thereby been implicated in several inflammatory pathologies. This review summarizes the major mechanisms and molecules involved in leukocyte-endothelial and leukocyte-platelet interactions in inflammation.
Endothelial cells; Adhesion; Leukocytes; Platelets; Inflammation
Sialostatin L (SialoL) is a secreted cysteine protease inhibitor identified in the salivary glands of the Lyme disease vector Ixodes scapularis. Here, we reveal the mechanisms of SialoL immunomodulatory actions on the vertebrate host. LPS-induced maturation of dendritic cells from C57BL/6 mice was significantly reduced in the presence of SialoL. Although OVA degradation was not affected by the presence of SialoL in dendritic cell cultures, cathepsin S activity was partially inhibited, leading to an accumulation of 10 KDa invariant chain intermediate (Ii-p10) in these cells. As a consequence, in vitro antigen-specific CD4+ T cell proliferation was inhibited in a time-dependent manner by SialoL and further studies engaging cathepsin S−/− or cathepsin L−/− dendritic cells confirmed that the immunomodulatory actions SialoL are mediated by inhibition of cathepsin S. Moreover, mice treated with SialoL displayed decreased early T cell expansion and recall response upon antigenic stimulation. Finally, SialoL administration during the immunization phase of experimental autoimmune encephalomyelitis in mice significantly prevented disease symptoms, which was associated with impaired IFN-γ and IL-17 production and specific T cell proliferation. These results illuminate the dual mechanism by which a human disease vector protein modulates vertebrate host immunity and reveals its potential in prevention of an autoimmune disease.
Dendritic cells; T cells; Autoimmunity; Antigen Presentation/Processing; Cell Proliferation
The ability of cells to attach to each other and to the extracellular matrix is of pivotal significance for the formation of functional organs and for the distribution of cells in the body. Several molecular families of proteins are involved in adhesion, and recent work has substantially improved our understanding of their structures and functions. Also, these molecules are now being targeted in the fight against disease. However, less is known about how their activity is regulated. It is apparent that among the different classes of adhesion molecules, the integrin family of adhesion receptors are unique in the sense that they constitute a large group of widely distributed receptors, they are unusually complex and most importantly their activities are strictly regulated from the inside of the cell. The activity regulation is achieved by a complex interplay of cytoskeletal proteins, protein kinases, phosphatases, small G proteins and adaptor proteins. Obviously, we are only in the beginning of our understanding of how the integrins function, but already now fascinating details have become apparent. Here, we describe recent progress in the field, concentrating mainly on mechanistical and structural studies of integrin regulation. Due to the large number of articles dealing with integrins, we focus on what we think are the most exciting and rewarding directions of contemporary research on cell adhesion and integrins.
Angiogenesis is indispensable during fracture repair, and vascular endothelial growth factor (VEGF) is critical in this process. CCN1 (CYR61) is an extracellular matrix signaling molecule that has been implicated in neovascularization through its interactions with several endothelial integrin receptors. CCN1 has been shown to be up-regulated during the reparative phase of fracture healing; however, the role of CCN1 therein remains unclear. Here, the regulation of CCN1 expression in osteoblasts and the functional consequences thereof were studied. Stimulation of osteoblasts with VEGF resulted in a dose- and time-dependent up-regulation of CCN1 mRNA and protein. An up-regulation of both cell surface-associated CCN1 as well as extracellular matrix-associated CCN1 in osteoblasts was found. The supernatant of VEGF-prestimulated osteoblasts was chemotactic for endothelial cells, increasing their migration and stimulated capillary-like sprout formation. These effects could be attributed to the presence of CCN1 in the osteoblast supernatant as they were prevented by an antibody against CCN1 or by small interfering RNA-mediated knockdown of osteoblast CCN1. Moreover, the supernatant of VEGF-prestimulated osteoblasts induced angiogenesis in Matrigel plugs in vivo in a CCN1-dependent manner. In addition, blockade of CCN1 prevented bone fracture healing in mice. Taken together, the present work demonstrates a potential paracrine loop consisting of the VEGF-mediated up-regulation of CCN1 in osteoblasts that attracts endothelial cells and promotes angiogenesis. Such a loop could be operative during fracture healing.
Neutrophil recruitment is an integral part of the immune response to infection as well as of inflammatory disorders. The process of neutrophil extravasation comprises a complex multistep cascade that is orchestrated by a tightly coordinated sequence of adhesive interactions with vessel wall endothelial cells. Adhesion receptors as well as signaling molecules in both neutrophils and endothelial cells regulate the recruitment of neutrophils into the site of inflammation or infection. The present review will focus on novel aspects with regards to the last step of neutrophil recruitment, namely the transmigration of neutrophils through endothelial cells.
Leukocyte recruitment to sites of infection or inflammation requires multiple adhesive events. While numerous players promoting leukocyte-endothelial interactions have been characterized, functionally important endogenous inhibitors of leukocyte adhesion have not been identified. Here, we describe the endothelial-derived secreted molecule, developmental endothelial locus-1 (Del-1), as an anti-adhesive factor that interferes with the integrin LFA-1-dependent leukocyte-endothelial adhesion. Endothelial Del-1-deficiency increased LFA-1-dependent leukocyte adhesion in vitro and in vivo. Del-1-/-mice displayed significantly higher neutrophil accumulation in LPS-induced lung inflammation in vivo, which was reversed in Del-1/LFA-1-double deficient mice. Thus, Del-1 is an endogenous inhibitor of inflammatory cell recruitment and could provide a basis for targeting leukocyte-endothelial interactions in disease.
Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and upregulated with hS100A7 during cutaneus inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific antibodies, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor of advanced glycated end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein coupled receptor. hS100A7-RAGE binding, signaling and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.
neutrophils; cytokine; cytokine receptor; chemotaxis; inflammation