title: Anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization.
abstract: IL-17-induced joint inflammation is associated with increased angiogenesis. However, the mechanism by which IL-17 mediates angiogenesis is undefined. Therefore, the pathologic role of CXCL1 and CXCL5 was investigated in arthritis mediated by local expression of IL-17, employing a neutralizing antibody to each chemokine. Next, endothelial chemotaxis was utilized to examine whether endothelial migration was differentially mediated by CXCL1 and CXCL5. Our results demonstrate that IL-17-mediated disease activity was not affected by anti-CXCL1 treatment alone. In contrast, mice receiving anti-CXCL5 demonstrated significantly reduced clinical signs of arthritis, compared to the mice treated with IgG control. Consistently, while inflammation, synovial lining thickness, bone erosion and vascularization were markedly reduced in both the anti-CXCL5 and combination anti-CXCL1 and 5 treatment groups, mice receiving anti-CXCL1 antibody had clinical scores similar to the control group. In contrast to joint FGF2 and VEGF levels, TNF-α was significantly reduced in mice receiving anti-CXCL5 or combination of anti-CXCL1 and 5 therapies compared to the control group. We found that, like IL-17, CXCL1-induced endothelial migration is mediated through activation of PI3K. In contrast, activation of NF-κB pathway was essential for endothelial chemotaxis induced by CXCL5. Although CXCL1 and CXCL5 can differentially mediate endothelial trafficking, blockade of CXCR2 can inhibit endothelial chemotaxis mediated by either of these chemokines. These results suggest that blockade of CXCL5 can modulate IL-17-induced inflammation in part by reducing joint blood vessel formation through a non-overlapping IL-17 mechanism.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, MSB 835S Wolcott Ave., E807-E809, Chicago, IL 60612, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Pickens
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Chamberlain
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.forename: Mark
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mandelin
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054365:Chemokine CXCL5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004121:Dimethyl Sulfoxide; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000098:blood supply / Q000166:cytology
chemical_list: D057134:Antibodies, Neutralizing; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D016207:Cytokines; D020381:Interleukin-17; D004121:Dimethyl Sulfoxide