title: Fas signaling in macrophages promotes chronicity in K/BxN serum-induced arthritis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  K/BxN serum-transfer arthritis was induced in a mouse line in which Fas was conditionally deleted in the myeloid lineage (Cre(LysM) Fas(flox/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.
  
  
  RESULTS
  Arthritis onset in Cre(LysM) Fas(flox/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Qi-Quan
authors.initials: QQ
authors.lastname: Huang
authors.forename: Robert
authors.initials: R
authors.lastname: Birkett
authors.forename: Renee E
authors.initials: RE
authors.lastname: Koessler
authors.forename: Carla M
authors.initials: CM
authors.lastname: Cuda
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002465:Cell Movement; D054365:Chemokine CXCL5 / Q000276:immunology; D002908:Chronic Disease; D016753:Interleukin-10 / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D019014:fas Receptor / Q000276:immunology*
chemical_list: D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; C491899:Fas protein, mouse; C556062:IL10 protein, mouse; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C053387:endoplasmin; D019014:fas Receptor; D016753:Interleukin-10