Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease

Abstract

Although there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin-C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin-C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of tenascin-C promotes joint inflammation in vivo in mice, and addition of exogenous tenascin-C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin-C induces synthesis of proinflammatory cytokines via activation of Toll-like receptor 4 (TLR4). Thus, we have identified tenascin-C as a novel endogenous activator of TLR4-mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.

Transcriptional Regulation of the Endogenous Danger Signal Tenascin-C: A Novel Autocrine Loop in Inflammation

“…Addition of exogenous tenascin-C stimulates cytokine synthesis in synovial membranes isolated from the joints of RA patients, an ex vivo model of human disease (3). In addition, tenascin-C expression is upregulated at both the mRNA and protein levels in synovial tissues in mouse models of joint inflammation (3,15), and tenascin-C is also arthritogenic in vivo when injected intra-articularly into mice (3). Furthermore, its activation of TLR4 is essential for driving persistent joint inflammation in vivo (3).…”

“…In addition, tenascin-C expression is upregulated at both the mRNA and protein levels in synovial tissues in mouse models of joint inflammation (3,15), and tenascin-C is also arthritogenic in vivo when injected intra-articularly into mice (3). Furthermore, its activation of TLR4 is essential for driving persistent joint inflammation in vivo (3). These data implicate tenascin-C as a key proinflammatory mediator in the RA joint.…”

The effect of high‐energy extracorporeal shock waves on hyaline cartilage of adult rats in vivo

“…Tenascin-C has been identified as a novel endogenous activator of Toll-like receptor (TLR) 4 that mediates persistent inflammation in arthritic joint disease. 38 The expression of tenascin-C is able to stimulate destructive joint diseases in vivo, and should therefore not be underestimated.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…TN-C is a ligand for several integrin receptors [119], as well as for TLR4 [120]. In synovial fibroblasts, TN-C has been shown to couple to proinflammatory cytokine expression via TLR4 activation [120]. TN-C is produced by a wide variety of cardiovascular cell types [118], including CF [94,117].…”