Toll-like receptor 2 controls acute immune complex-driven arthritis by regulating the inhibitory Fcγ receptor IIB (original) (raw)

2013, Arthritis & Rheumatism

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, Fc␥ receptor (Fc␥R) 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 Fc␥R-driven disease. Ex vivo study of the macrophage inflammatory phenotype revealed increased production of tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6) despite similar levels of IL-10, along with a significant increase in Fc␥R-specific response, in TLR-2 ؊/؊ mouse macrophages early in the disease. Although distinct Fc␥R messenger RNA expression was not affected, cell surface protein expression of the inhibitory Fc␥RIIB in TLR-2 ؊/؊ naive primary macrophages was specifically diminished, resulting in a higher proinflammatory response. Accordingly, TLR-2 stimulation specifically up-regulated Fc␥RIIB, but not the activating Fc␥R, on macrophages. Conclusion. TLR-2 regulates acute immune complex-driven arthritis by controlling macrophage Fc␥R response. Our findings indicate that the protective role of TLR-2 is extended beyond its previously described role in promoting Treg cells during T cellmediated arthritis. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and progressive cartilage and bone destruction in multiple joints. The pathogenesis of RA is grounded in a complex network of the components of innate and adaptive immune systems. Among the innate immune receptors, Toll-like receptors (TLRs) have recently gained attention due to a growing body of evidence indicating their involvement in RA. TLRs are a family of pattern-recognition receptors evolved to recognize conserved microbe-associated molecular patterns. Increased expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RA synovial tissue supports the idea that these receptors are relevant in the disease (1-3). Some TLRs can be activated by endoge