Background/Purpose: Interleukin-17 Receptor D (IL-17RD) otherwise known as similar expression of fibroblast growth factor genes (SEF) is often described as an inhibitor of multiple signaling cascades. IL-17RD is a member of the IL-17 receptor family. In contrast to the other IL-17 receptors, IL-17RA, -RB, -RC and -RE, little is known about the ligand and function of IL-17RD. We hypothesized that IL-17RD is a brake that needs to be removed in order to develop auto-immune arthritis. However, the functional role of IL-17RD in auto-immune arthritis is still unknown and is the purpose of this study.

Methods: Human synovial fibroblasts from Rheumatoid Arthritis (RA) patients were stimulated with tumor necrosis factor α (TNFα), interleukin 1 β (IL-1β) or IL-17A for multiple time points. IL-17RD expression levels were measured via qPCR. Collagen induced arthritis (CIA) was induced in IL-17RD knockout mice and wildtype littermates. At days 1 and 21, mice were immunized intradermally with chicken collagen type II in complete Freund’s adjuvant (CFA). Mice were scored 3 times a week for clinical disease defined as swollen joints with a maximum score of 8. Due to ethical reasons, mice were removed from the experiments when they reached a score of 6. CD4⁺ memory T cells, CD8⁺ memory T cells, CD19⁺ B cells and monocytes were isolated from WT spleens and analysed for IL-17RD expression. Blood neutrophil migration assays were performed in vitro using WT and IL-17RD deficient (IL-17RD KO) mouse synovial fibroblasts.

Results: We show that IL-17RD is regulated by pro-inflammatory cytokines and plays a role in the development of collagen-induced arthritis (CIA). IL-17RD expression was decreased in human synovial fibroblasts from rheumatoid arthritis (RA) patients upon stimulation with TNFα or IL-1β but not IL-17A. Interestingly, CIA incidence was significantly reduced in IL-17RD knockout (IL-17RD KO) mice compared to wildtype littermates (C57BL/6N) without affecting CIA severity in mice developing clinical manifest disease. Besides very low or absent IL-17RD expression in immune cells, no altered cytokine production was observed in LPS stimulated monocytes or αCD3 and αCD28 activated CD4+ T cells from IL-17RD KO mice versus WT controls. However, lower production of CXCL2 was detected by IL-17RD deficient synovial fibroblasts when stimulated with TNFα and IL-17A. Additionally, less neutrophils were attracted by these IL-17RD deficient synovial fibroblasts.

Conclusion: These data show the downregulation of baseline IL-17RD expression by pro-inflammatory cytokines in synovial fibroblasts and how IL-17RD deficiency reduces CIA incidence. This indicates that IL-17RD is likely a brake that is removed in an inflammatory environment but contradictorily lowers the chance of developing auto-immune arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-17-receptor-d-il-17rd-is-regulated-by-pro-inflammatory-cytokines-and-plays-a-role-in-the-development-of-collagen-induced-arthritis/