Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum–Induced Arthritis
Version of Record online: 30 DEC 2013
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 1, pages 68–77, January 2014
How to Cite
Huang, Q.-Q., Birkett, R., Koessler, R. E., Cuda, C. M., Haines, G. K., Jin, J.-P., Perlman, H. and Pope, R. M. (2014), Fas Signaling in Macrophages Promotes Chronicity in K/BxN Serum–Induced Arthritis. Arthritis & Rheumatology, 66: 68–77. doi: 10.1002/art.38198
- Issue online: 30 DEC 2013
- Version of Record online: 30 DEC 2013
- Accepted manuscript online: 24 SEP 2013 09:48AM EST
- Manuscript Accepted: 10 SEP 2013
- Manuscript Received: 29 MAR 2013
A nonapoptotic role of Fas signaling has been implicated in the regulation of inflammation and innate immunity. This study was undertaken to elucidate the contribution of Fas signaling in macrophages to the development of arthritis.
K/BxN serum–transfer arthritis was induced in a mouse line in which Fas was conditionally deleted in the myeloid lineage (CreLysMFasflox/flox mice). The arthritis was assessed clinically and histologically. Expression of interleukin-1β (IL-1β), CXCL5, IL-10, IL-6, and gp96 was determined by enzyme-linked immunosorbent assay. Bone marrow–derived macrophages were activated with IL-1β and gp96. Cell phenotype and apoptosis were analyzed by flow cytometry.
Arthritis onset in CreLysMFasflox/flox mice was comparable with 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 Toll-like receptor 2 (TLR-2) ligand gp96 and the neutrophil chemotactic chemokine CXCL5, and enhanced expression of IL-10. Activation with IL-1β or gp96 induced increased IL-10 expression in Fas-deficient murine macrophages compared with control macrophages. IL-10 suppressed IL-6 and CXCL5 expression induced by IL-1β plus gp96. IL-1β–mediated activation of ERK, which regulates IL-10 expression, was increased in Fas-deficient mouse macrophages.
Taken together, our findings indicate that impaired Fas signaling results in enhanced expression of antiinflammatory IL-10 and reduced expression of gp96, and these effects are associated with accelerated resolution of inflammation during the chronic phase of arthritis. These observations suggest that strategies to reduce endogenous TLR ligands and increase IL-10 may be beneficial in the treatment of rheumatoid arthritis.