Abstract
Abstract Fas/Fas ligand (FasL)-mediated apoptotic and non-apoptotic processes have long been known to regulate inflammatory responses. FasL exerts biological functions through two different forms in vivo: a membrane-bound FasL (mFasL) and soluble FasL (sFasL). It is unknown whether sFasL contributes to the pathogenesis of joint inflammation. Here, we found that sFasL triggered soluble CX3CL1 generation from fibroblast-like synovial cells by enhancing proteinase activity, which induced CX3CR1+ joint immune cell migration and chemokine production in an apoptosis-independent manner in mice and humans. Murine and human synovial cells deficient for Fas were minimally affected by sFasL-mediated induction of joint inflammation. Blockade of sFasL or CX3CR1 attenuated antibody-induced arthritis in mice. Therefore, we propose a novel function of sFasL in regulating joint inflammation via the CX3CL1-CX3CR1 axis, a process that occurs independently of Fas ligation. This novel axis may be a useful therapeutic target for arthritis.
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