title: 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.
authors: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK. k.midwood@imperial.ac.uk
authors: Kim
authors: K
authors: Midwood
authors: Sandra
authors: S
authors: Sacre
authors: Anna M
authors: AM
authors: Piccinini
authors: Julia
authors: J
authors: Inglis
authors: Annette
authors: A
authors: Trebaul
authors: Emma
authors: E
authors: Chan
authors: Stefan
authors: S
authors: Drexler
authors: Nidhi
authors: N
authors: Sofat
authors: Masahide
authors: M
authors: Kashiwagi
authors: Gertraud
authors: G
authors: Orend
authors: Fionula
authors: F
authors: Brennan
authors: Brian
authors: B
authors: Foxwell
mesh_terms: D000818:Animals; D001168:Arthritis / Q000209:etiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D017434:Protein Structure, Tertiary; D019063:Tenascin / Q000737:chemistry / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D019063:Tenascin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4