Objective: To study the role of TLR2 and 4 in onset of joint inflammation and cartilage destruction during immune complex mediated arthritis (ICA) and its relation with Fc[gamma]R expression.
Methods: ICA was induced in knee joints of TLR2- /- and TLR4-/- mice and their wildtype controls. Joint inflammation and cartilage destruction was measured in the knee joint using histology. mRNA levels were determined in synovial specimen and macrophages using Q- PCR and cytokine protein levels in synovial washouts using Bioplex.
Results:Joint inflammation and cartilage destruction was not different in arthritic TLR2-/- and WT mice. In contrast at day 1 after ICA induction, joint swelling and PG depletion in knee joints of TLR4-/- mice was significantly lower ( inflammation 68-79% and PG depletion 27-76%), when compared to WT controls. Cytokine production at this time-point was markedly reduced in TLR4-/- mice ( IL-1, IL-6, MIP-1a and KC with 49%,72%,68% and 84% respectively). In arthritic synovia of TLR4-/- but also after injection of the antigen PLL- lysozyme alone, mRNA levels of Fc[gamma]R but also the FcgR regulating cytokine IL-10 were significantly lower. Stimulation of peritoneal macrophages with PLL-lys up- regulated mRNA levels of Fc[gamma]R and IL-10 whereas neutralisation by anti-IL-10 antibodies largely blocked FcgR upregulation. At day 4 joint inflammation and cartilage destruction was comparable in TLR4-/- and WT controls.
Conclusions:TLR 4 regulates early onset of joint inflammation and cartilage destruction during immune complex mediated arthritis by upregulation of Fc[gamma]R expression and enhanced cytokine production. TLR4 mediated up-regulation of Fc[gamma]R is largely mediated by IL-10.
- Fcgamma receptors
- cartilage destruction
- experimental arthritis
- joint inflammation
- toll-like receptors