Article abstract
Nature Medicine 15, 774 - 780 (2009)
Published online: 28 June 2009 | doi:10.1038/nm.1987
Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease
Kim Midwood1, Sandra Sacre1, Anna M Piccinini1, Julia Inglis1, Annette Trebaul1,3, Emma Chan1,3, Stefan Drexler1,3, Nidhi Sofat1, Masahide Kashiwagi1, Gertraud Orend2, Fionula Brennan1 & Brian Foxwell1
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.
- Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
- Institut National de la Santé et de la Recherche Médicale U682, Université Strasbourg, Strasbourg, France.
- Current addresses: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland (A.T.); Institute of Child Health, London, UK (E.C.); Université de Lausanne, Epalinges, Switzerland (S.D.).
Correspondence to: Kim Midwood1 e-mail: k.midwood@imperial.ac.uk
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