(The) role of soluble Fas ligand in rheumatoid arthritis

Abstract

Fas-Fas ligand (FasL) interactions play critical roles in the development of rheumatoid arthritis (RA), however, their roles still remain unclear in the antibody-induced arthritis (AIA) model, which mainly represents the effect phase of RA. In this study, we attempted to uncover the biological functions of the Fas-FasL interactions in AIA using the K/BxN serum transfer model. Unexpectedly, FasL-deficient (gld/gld) mice were highly resistant to the development of arthritis, whereas, there were no differences between the Fas-deficient (lpr/lpr) mice and B6 mice which included ankle swelling and clinical index. Interestingly, only the soluble form of FasL (sFasL) seemed to be essential for the development of joint inflammation via non-apoptotic pathway. Furthermore, we observed that sFasL-producing F4/80+ macrophages, c-kit+ mast cells and iNKT cells promote joint inflammation during arthritis. Moreover, gld/gld mice decreased pro-inflammatory chemokines and cytokines (Mip-1α, MCP-1, IP-10, IL-4 and IFN-γ), compared to B6 and lpr/lpr mice, whereas anti-inflammatory cytokine, TGF-β increased in gld/gld mice. We discovered that sFasL directly promoted the production of CX3CL1 by synoviocytes, a well-known strong chemoattractant, and which, in turn, induced the expression of several chemokines such as Mip-1α, MCP-1 and IP-10 by immune cells, resulting in the recruitment of inflammatory cells into the joint cavity. Taken together, this study proposes that sFasL may function as a key pro-inflammatory mediator in the effector phase of RA. Furthermore, Fas/FasL double deficient (lpr/gld) mice showed resistance in joint inflammation, and these mice restored arthritis with the treatment of sFasL despite the lack of Fas. Also, immune cells from lpr/lpr mice produced chemokines when I treated sFasL as immune cells from B6 mice, confirming the sFasLs Fas-independent pro-inflammatory action in my model. Also, I demonstrated that the blocking antibody against FasL was remarkably effective in both the prevention and treatment for arthritis. Moreover, this study also confirmed these results using RA patients samples and human synoviocytes cell line. In conclusion, these data clearly showed a great potential of sFasL as a therapeutic target for RA.