Expression of Toll-like Receptors and Their Signaling Pathways in Rheumatoid Synovitis

Abstract

RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.

Toll-like Receptor

“…In osteoarthritic synovium, TLRs and the adaptors were only very weakly immuno-labeled in vascular, lining and inflammatory cells. 36 Taken together, the data suggested that RA synovium well-equipped with TLRs and adaptors, which implies high and prompt responsiveness to the external and internal stimuli, namely, PAMPs and DAMPs.…”

“…In addition to the presence of immunoreactive cells of TLR2 and 4 91 as well as those of TLR 3 and 7 152 in synovial lining and sublining intima, well equipment of TLR1, 2, 3, 4, 5, 6 and 9 in monocytes/macrophages, DCs, B cells and T cells in RA synovium were observed by immunohistochemisty. 36 Marked inflammation in RA synovium can produce a variety of mediators and DAMPs, which may influence expression of TLRs in the diseased tissues, being with various states of maturation and/or activation of each cell type. Thus, it may contribute to different profiles of TLR expressions between inflamed RA tissues and in vitro studies with blood samples.…”

TRAF6 regulates the effects of polarized maturation of tolerability: Marrow-derived dendritic cells on collagen-induced arthritis in mice

“…TRAF6 is a key to TLR activation and intersecting signaling pathways activated the NF-κB and mitogen-activated protein kinase pathways. TRAF6 assists in the maturity of DC-mediated signal transduction and is a key to DC formation, activation, and maturation (20)(21)(22). Thus, to explore specific interventions of TRAF6 expression is essential, which inhibits DC maturation, reconstructs RA immune tolerance, and plays a therapeutic role (23,24).…”

Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?

“…mRNA in RA > OA or non arthritic joints, at synovial lining, sites of attachment and invasion into cartilage or bone, around small vessels and in areas of infiltrating lymphocytes (fibroblasts not macrophages or T cells) yes (Seibl et al, 2003) Protein in RA > OA or healthy joints in synovial lining, sublining and perivascular regions nd Protein in RA blood monocytes, tissue macrophages yes (Iwahashi et al, 2004;Huang et al, 2007) Protein in fibroblasts from RA > OA joints > healthy skin yes TLR3 mRNA and protein in RA > OA or healthy synovium, in fibroblasts of the synovial lining and sublining, and in the perivascular areas yes (Brentano et al, 2005;Roelofs et al, 2005) Protein in fibroblasts from early RA > OA or healthy synovium yes (Ospelt et al, 2008) TLR4 mRNA in RA synovial tissue, protein in DCs and macrophages but not T cells or fibroblasts from RA joint yes ) (Tamaki et al, 2011) (Huang et al, 2007) Protein in synovial tissue from RA > OA > healthy joints, in early and longstanding RA yes ) (Ospelt et al, 2008) Protein in RA synovial fibroblasts yes Wu et al, 2010) TLR5 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) TLR6 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) TLR7 Protein in RA synovium > OA or healthy joints yes (Roelofs et al, 2005;Roelofs et al, 2009) TLR9 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) nd = not determined F= function = the ability of the TLR to respond to its cognate ligand in each cell/tissue type Further studies using ex vivo human disease models have provided evidence of a functional role for TLRs in driving inflammation in RA. Adenoviral over expression of dominant negative Myd88, an adaptor molecule required for signalling by all TLRs except TLR3, inhibited cytokine synthesis in RA synovial cells .…”

“…Significant up-regulation of a number of TLRs was observed in both synovial tissue and circulating immune cells isolated from RA patients. (Tamaki et al, 2011).…”