Background/Purpose: A non-apoptotic role for Fas signaling has been implicated in the regulation of inflammation and innate immunity.  These studies were performed to elucidate the role of Fas signaling on macrophages in the development of arthritis. 

Methods: K/BxN serum transfer arthritis was induced in a mouse line with Fas conditionally deleted in the myeloid lineage (Fas ^f/f, LyzM^cre).  The arthritis was assessed clinically and histologically.  IL-1b, CXCL5, IL-10, IL-6 and gp96 expression was determined by ELISA.  Bone marrow derived macrophages were activated by IL-1b and gp96.  Cells were analyzed for phenotype and apoptosis by flow cytometry.   

Results: The onset of arthritis in Fas ^f/f, LyzM^cre mice was comparable to that observed in control mice, however, resolution was accelerated during the chronic phase.  The attenuated arthritis was associated with reduced articular expression of the endogenous TLR2 ligand gp96 and the neutrophil chemokine CXCL5, and the enhanced expression of IL-10.  Activation with IL-1b or gp96 induced increased IL-10 in Fas deficient, compared with control, macrophages.  IL-10 suppressed IL-1b plus gp96 induced IL-6 and CXCL5.  IL-1b-mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient macrophages.

Conclusion: Together, our observations suggest that impaired Fas signaling results in the enhanced expression of anti-inflammatory IL-10 and reduced gp96, which are associated with accelerated resolution of inflammation in the chronic phase of arthritis.  These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fas-signaling-in-macrophages-promotes-chronicity-in-kbxn-serum-transfer-induced-arthritis/