Abstract
OBJECTIVE: To study the role of Toll-like receptor (TLR)2 and 4 in the onset of joint inflammation and cartilage destruction during immune complex-mediated arthritis (ICA), and its relationship with FcgammaR expression. MATERIALS AND METHODS: ICA was induced in knee joints of TLR2-/- and TLR4-/- mice and their wild-type controls. Joint inflammation and cartilage destruction were measured in the knee joint using histology. mRNA levels were determined in synovial specimens and macrophages using quantitative polymerase chain reaction and cytokine protein levels in synovial washouts using Bioplex. RESULTS: Joint inflammation and cartilage destruction were not different in arthritic TLR2-/- and wild-type mice. By contrast, at day 1 after ICA induction, joint swelling and proteoglycan depletion in knee joints of TLR4-/- mice were considerably lower (inflammation 68-79% and proteoglycan depletion 27-76%) when compared with wild-type controls. Cytokine production at this time point was markedly reduced in TLR4-/- mice (interleukin (IL)1, IL6, macrophage inflammatory chemokine (MIP)-1alpha and keratinocyte-derived chemokine 49%, 72%, 68% and 84%, respectively). In arthritic synovia of TLR4-/- mice, and also after injection of the antigen poly-l-lysine (PLL) lysozyme alone, mRNA levels of FcgammaR, and the FcgammaR regulating cytokine IL10 were considerably lower. Stimulation of peritoneal macrophages with PLL lysozyme up regulated mRNA levels of FcgammaR and IL10, whereas neutralisation by anti-IL10 antibodies largely blocked FcgammaR up regulation. At day 4, joint inflammation and cartilage destruction were comparable in TLR4-/- mice and wild-type controls. CONCLUSION: TLR4 regulates early onset of joint inflammation and cartilage destruction during ICA arthritis by up regulation of FcgammaR expression and enhanced cytokine production. TLR4-mediated up regulation of FcgammaR is largely mediated by IL10.