title: Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17-dependent arthritis in mice.
abstract: OBJECTIVE
  Increasing evidence indicates the involvement of Toll-like receptors (TLRs) in the progression of arthritis; however, the contribution of the two signaling pathways used by TLRs, which are mediated by myeloid differentiation factor 88 (MyD88) and TRIF, remains unclear. The objective of this study was to investigate the specific roles of MyD88 and TRIF in chronic experimental arthritis and the accompanying adaptive immune responses.
  
  
  METHODS
  Chronic arthritis was induced in wild-type, MyD88(-/-) , and Trif(lps2)  (TRIF(-/-) ) mice by repetitive intraarticular injections of streptococcal cell wall (SCW) fragments. SCW-specific T cell and B cell responses, joint swelling, and histopathologic changes were analyzed during chronic arthritis.
  
  
  RESULTS
  Both MyD88 and TRIF pathways contributed to antigen-specific T cell proliferation and antibody production, with the MyD88 pathway playing the dominant role. The severity of joint swelling and synovial inflammation, as well as the histopathologic damage to cartilage and bone, was strongly dependent on MyD88 signaling, whereas TRIF was redundant. MyD88 signaling was critical for the development of pathogenic T cell response (i.e., interleukin-17 [IL-17] production) in response to SCW antigen. Interestingly, when the T cell-dependent phase was prolonged, TRIF signaling appeared to down-regulate bone erosion, an effect accompanied by an inhibitory effect on IL-17 production.
  
  
  CONCLUSIONS
  This study reveals a central role of MyD88 and a counterregulatory function of TRIF in T cell-driven arthritis. The findings provide a rationale for a pathway-specific interference in order to block the pathogenic features and to preserve or stimulate the beneficial aspects of TLR signaling.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.abdollahiroodsaz@reuma.umcn.nl
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Monique M
authors.initials: MM
authors.lastname: Helsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Walgreen
authors.forename: Liduine A
authors.initials: LA
authors.lastname: van den Bersselaar
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D056704:Adaptive Immunity; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D007596:Joints / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020381:Interleukin-17; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse