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 wildtype, 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.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 features and to preserve or stimulate the beneficial aspects of TLR signaling.

Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: In vitro, ex vivo studies

“…Given that MyD88 is the key regulatory cofactor that transduces TLR signals to induce matrix-degrading enzyme expression and ECM degradation in articular chondrocytes (Abdollahi-Roodsaz et al, 2011; Liu-Bryan and Terkeltaub, 2010), we examined the potential for MyD88 i to antagonize catabolic effects induced by LPS and IL-1 in bovine IVD cells. In initial experiments using monolayer cultures with different concentrations of peptide inhibitor of MyD88 (MyD88 i ), we found that 100 μM of MyD88 i is a minimal dose demonstrating maximal effects.…”

“…TLRs have also been shown to upregulate production of collagenases (MMP-1 and MMP-13), and inducible nitric oxide synthase (Kokkinos et al, 1997), an enzyme that catalyzes the production of pro-inflammatory nitric oxide (NO) (Campo et al, 2011; Kim et al, 2006). The mechanism responsible for these downstream effects is not fully understood, but the MyD88 pathway has been shown to be an integral part of TLR activity (Abdollahi-Roodsaz et al, 2011). …”

“…Activation of the TLR-2/MyD88 pathways has also been associated with the induction of pro-inflammatory cytokines such as IL-6 and destructive tissue MMPs in peripheral arthritis models (Kim et al, 2006; Papathanasiou et al, 2011). Most recently, PG synthesis was enhanced and matrix-degrading enzyme expression suppressed in MyD88 knockout mice, suggesting that MyD88 pathway inhibition may be a potential therapeutic treatment option for inflammatory cartilage disease (Abdollahi-Roodsaz et al, 2011). …”

Designing Anti-inflammatory Drugs from Parasitic Worms: A Synthetic Small Molecule Analogue of the Acanthocheilonema viteae Product ES-62 Prevents Development of Collagen-Induced Arthritis

“…Moreover, the recent use of MyD88-deficient mice has shown this signaling element to be crucial to development of IL-17-driven arthritis, both in terms of initiation of pathogenic IL-17 responses and also the severity of joint inflammation and pathology. 17−20,54,55 …”

Synovium and the Innate Inflammatory Network in Osteoarthritis Progression

“…The physiologic impact of this observation warrants further investigation. It should be noted that innate immune effector mechanisms can mediate tissue repair, with protective effects on bone erosion described by Toll/interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) modulation of IL-17 in the T cell activation-driven SCW model inflammatory arthritis [57]. …”