Destructive Role of Myeloid Differentiation Factor 88 and Protective Role of TIR-Containing Adaptor Inducing Interferon β in IL-17-Dependent Arthritis
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Abdollahi-Roodsaz, Shahla, van de Loo, Fons, Koenders, Marije, Helsen, Monique, Walgreen, Brigitte, van den Bersselaar, Leduine, Arntz, Onno, Takahashi, Nozomi, Joosten, Leo and van den Berg, Wim (2011) Destructive Role of Myeloid Differentiation Factor 88 and Protective Role of TIR-Containing Adaptor Inducing Interferon β in IL-17-Dependent Arthritis. Arthritis & Rheumatism. ISSN 0004-3591
Abstract
Objective. Increasing evidence indicates the involvement of Toll-like receptors (TLRs) in progression of arthritis; however, the contribution of the two signaling pathways utilized by TLRs, mediated by myeloid differentiation factor 88 (MyD88) and Toll/interleukin-1 receptor domain-containing adaptor inducing interferon β (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 intra-articular injections of Streptococcal cell wall (SCW) fragments. SCW-specific T and B cell responses as well as joint swelling and histopathology 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 histopathological 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 downregulate 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 cell-driven arthritis. The findings provide a rationale for a pathway-specific interference in order to block the pathogenic and to preserve or stimulate the beneficial aspects of TLR signaling.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing);On personal web site or secure external website at authors institution; Publisher's version/PDF cannot be used |
| Keywords: | IL17, MyD88, TRIF, arthritis, mouse |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6152 |