IL-17RA signaling amplifies antibody-induced arthritis.
OBJECTIVE
To investigate the role of IL-17RA signaling in the effector phase of inflammatory arthritis using the K/BxN serum-transfer model.


METHODS
Wild-type and Il17ra(-/-) mice were injected with serum isolated from arthritic K/BxN mice and their clinical score was recorded daily. Mice were also harvested on days 12 and 21 and ankles were analyzed for cytokine and chemokine mRNA expression by qPCR on day 12 and for bone and cartilage erosions by histology on day 21, respectively. The induction of cytokine and chemokine expression levels by IL-17A in synovial-like fibroblasts was also analyzed using qPCR.


RESULTS
Il17ra(-/-) mice were partially protected from clinical signs of arthritis and had markedly fewer cartilage and bone erosions. The expression of several pro-inflammatory mediators, including the chemokines KC/CXCL1, MIP-2/CXCL2, LIX/CXCL5 MIP-1γ/CCL9, MCP-3/CCL7, MIP-3α/CCL20, the cytokines IL-1β, IL-6, RANKL and the matrix metalloproteinases MMP2, MMP3, and MMP13 were decreased in the ankles of Il17ra(-/-) mice compared to wild-type mice. Many of these proinflammatory genes attenuated in the ankles of Il17ra(-/-) mice were shown to be directly induced by IL-17A in synovial fibroblasts in vitro.


CONCLUSIONS
IL-17RA signaling plays a role as an amplifier of the effector phase of inflammatory arthritis. This effect is likely mediated by direct activation of synovial fibroblasts by IL-17RA to produce multiple inflammatory mediators, including chemokines active on neutrophils. Therefore, interrupting IL-17RA signaling maybe a promising pharmacological target for the treatment of inflammatory arthritis.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Christian D
CD
Sadik
Nancy D
ND
Kim
Elena
E
Alekseeva
Andrew D
AD
Luster
D000818:Animals; D000906:Antibodies / Q000009:adverse effects* / Q000097:blood / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D013582:Synovial Fluid / Q000378:metabolism
D000906:Antibodies; C491673:Il17ra protein, mouse; D018836:Inflammation Mediators; D053245:RANK Ligand; D053722:Receptors, Interleukin-17; D019278:Matrix Metalloproteinase 3