Toll‐like Receptor 2 Controls Acute Immune Complex–Driven Arthritis in Mice by Regulating the Inhibitory Fcγ Receptor IIB. Issue 10 (24th September 2013)

• Record Type: Journal Article
• Authors: Abdollahi‐Roodsaz, Shahla; Koenders, Marije I.; Walgreen, Birgitte; Bolscher, Judith; Helsen, Monique M.; van den Bersselaar, Liduine A.; van Lent, Peter L.; van de Loo, Fons A. J.; van den Berg, Wim B.
• Is Part Of: Arthritis and rheumatism. Volume 65:Issue 10(2013:Oct.)
• Page Start: 2583
• Page End: 2593
• Publication Date: 2013-09-24
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; Arthritis -- Periodicals; Rheumatic Diseases -- Periodicals; Rhumatisme -- Périodiques; Arthrite -- Périodiques; 616.72
• DOI: 10.1002/art.38087
• Languages: English
• ISSNs: 0004-3591

Abstract

Abstract : 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, Fcγ receptor (FcγR) 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 FcγR‐driven disease. Ex vivo study of the macrophage inflammatory phenotype revealed increased production of tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) despite similar levels of IL‐10, along with a significant increase in FcγR‐specific response, in TLR‐2 −/− mouse macrophages early in the disease. Although distinct FcγR messenger RNA expression was not affected, cell surface protein expression of the inhibitory FcγRIIB in TLR‐2 −/− naive primary macrophages was specifically diminished, resulting in a higher proinflammatory response. Accordingly, TLR‐2 stimulation specifically up‐regulated FcγRIIB, but not the activating FcγR, on macrophages. Conclusion: TLR‐2 regulates acute immune complex–driven arthritis by controlling macrophage FcγR 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.