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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

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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Correspondence to Kim Midwood.

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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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