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

Nature Medicine volume 15, pages 774–780 (2009)Cite this article

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.

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Figure 1: Accelerated resolution of acute inflammation in Tnc−/− mice.
Figure 2: Synovial inflammation is induced in Tnc−/− mice upon injection of antigen.
Figure 3: Synovial inflammation subsides rapidly in Tnc−/− mice.
Figure 4: Tnc−/− mice are protected from tissue destruction, and tenascin-C induces cytokine synthesis in primary human cells.
Figure 5: The FBG domain of tenascin-C mediates stimulation of cytokine synthesis in vivo and in vitro.
Figure 6: FBG-mediated cytokine synthesis is MyD88 and TLR4 dependent.

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Acknowledgements

This paper is dedicated to B. Foxwell, an inspirational colleague and a good friend, who will be sadly missed. We thank R. Best for processing tissue, D. Essex for immunohistology and C. ffrench-Constant (University of Edinburgh) for the gift of the Tnc−/− mice. This work was funded by the Arthritis Research Campaign, The Kennedy Institute of Rheumatology Trustees and a UK Medical Research Council New Investigators Research Grant awarded to K.M. We are also grateful for support from the UK National Institute for Health Research Biomedical Research Centre funding scheme. G.O. was supported by Institut National du Cancer–Institut National de la Santé et de la Recherche Médicale and a Contrat d'interface with the Hospital Hautepierre.

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Author notes

  1. Annette Trebaul, Emma Chan & Stefan Drexler

    Present address: Current addresses: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland (A.T.); Institute of Child Health, London, UK (E.C.); Université de Lausanne, Epalinges, Switzerland (S.D.).,

Authors and Affiliations

  1. Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK

    Kim Midwood, Sandra Sacre, Anna M Piccinini, Julia Inglis, Annette Trebaul, Emma Chan, Stefan Drexler, Nidhi Sofat, Masahide Kashiwagi, Fionula Brennan & Brian Foxwell

  2. Institut National de la Santé et de la Recherche Médicale U682, Université Strasbourg, Strasbourg, France

    Gertraud Orend

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Midwood, K., Sacre, S., Piccinini, A. et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15, 774–780 (2009). https://doi.org/10.1038/nm.1987

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