Shift from toll‐like receptor 2 (TLR‐2) toward TLR‐4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR‐4–mediated interleukin‐17 production

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Abstract
Objective Toll-like receptors (TLRs) may activate innate and adaptive immune responses in rheumatoid arthritis (RA) through recognition of microbial as well as endogenous ligands that have repeatedly been found in arthritic joints. The objective of this study was to investigate the involvement of TLR-2 and TLR-4 in the development of chronic destructive streptococcal cell wall (SCW)–induced arthritis, in which interleukin-1 (IL-1)/IL-17–dependent T cell–driven pathologic changes replace the macrophage-driven acute phase. Methods Chronic SCW arthritis was induced by 4 repeated intraarticular injections of SCW fragments in wild-type, TLR-2−/−, and TLR-4−/− mice. Clinical, histopathologic, and immunologic parameters of arthritis were evaluated. Results The TLR-2 dependency of joint swelling during the acute phase was shifted to TLR-4 dependency during the chronic phase. Persistent joint inflammation in the latter phase of the model was significantly suppressed in TLR-4−/− mice. In the chronic phase, TLR-4 actively contributed to matrix metalloproteinase (MMP)–mediated cartilage destruction and to osteoclast formation, since the expression of the MMP-specific aggrecan neoepitope VDIPEN and the osteoclast marker cathepsin K was significantly reduced in TLR-4−/− mice. Furthermore, TLR-4−/− mice expressed less IL-1β, tumor necrosis factor α, IL-6, and IL-23, cytokines that are implicated in IL-17 production. Accordingly, SCW-specific IL-17 production was found to be dependent on TLR-4 activation, since T cells from arthritic TLR-4−/− mice produced markedly less IL-17 upon SCW stimulation, whereas interferon-γ production remained unaffected. Conclusion These data indicate the involvement of TLR-4 in the chronicity and erosive character of arthritis coincident with the antigen-specific IL-17 response. The high position of TLR-4 in the hierarchy of erosive arthritis provides an interesting therapeutic target for RA.