Toll-like receptor 2 controls acute immune complex-driven arthritis in mice by regulating the inhibitory Fcgamma receptor IIB
SourceArthritis and Rheumatism, 65, 10, (2013), pp. 2583-2593
Article / Letter to editor
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Arthritis and Rheumatism
SubjectNCMLS 1: Infection and autoimmunity N4i 4: Auto-immunity, transplantation and immunotherapy
OBJECTIVE: Previous studies have demonstrated a protective role of Toll-like receptor 2 (TLR-2) and a proinflammatory function of TLR-4 during chronic T cell-driven arthritis. The involvement of TLRs in T cell-independent arthritic processes, however, remains unclear. This study was undertaken to determine the functional significance of TLR-2 and TLR-4 in T cell-independent immune complex-driven arthritis. METHODS: Serum-transfer arthritis was induced in wild-type and TLR-deficient mice by intraperitoneal injections of arthritogenic K/BxN mouse serum. Arthritis was assessed macroscopically and by histologic analysis. The influence of TLR-2 on macrophage cytokine profile, Fcgamma receptor (FcgammaR) expression, and response to immune complexes was determined. RESULTS: While TLR-4, unexpectedly, did not play any significant role, TLR-2 deficiency accelerated the onset and markedly increased the severity of acute immune complex-driven arthritis in mice. TLR-2 deficiency resulted in a substantial increase in joint inflammation, bone erosion, and cartilage pathology, indicating a protective function of TLR-2 in passive FcgammaR-driven disease. Ex vivo study of the macrophage inflammatory phenotype revealed increased production of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) despite similar levels of IL-10, along with a significant increase in FcgammaR-specific response, in TLR-2-/- mouse macrophages early in the disease. Although distinct FcgammaR messenger RNA expression was not affected, cell surface protein expression of the inhibitory FcgammaRIIB in TLR-2-/- naive primary macrophages was specifically diminished, resulting in a higher proinflammatory response. Accordingly, TLR-2 stimulation specifically up-regulated FcgammaRIIB, but not the activating FcgammaR, on macrophages. CONCLUSION: TLR-2 regulates acute immune complex-driven arthritis by controlling macrophage FcgammaR response. Our findings indicate that the protective role of TLR-2 is extended beyond its previously described role in promoting Treg cells during T cell-mediated arthritis.
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