Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17-dependent arthritis in mice

作者：Abdollahi Roodsaz Shahla^*; van de Loo Fons A J; Koenders Marije I; Helsen Monique M; Walgreen Birgitte; van den Bersselaar Liduine A; Arntz Onno J; Takahashi Nozomi; Joosten Leo A B; van den Berg Wim B

来源：Arthritis and Rheumatism, 2012, 64(6): 1838-1847.

DOI：10.1002/art.34328

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 Triflps2 (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 celldependent phase was prolonged, TRIF signaling appeared to down-regulate bone erosion, an effect accompanied by an inhibitory effect on IL-17 production. Conclusion This study reveals a central role of MyD88 and a counterregulatory function of TRIF in T celldriven 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.

• 出版日期2012-6