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

By K. Midwood, S. Sacre, A. Piccinini, J. Inglis, A. Trébaul, E. Chan, S. Drexler, N. Sofat, M. Kashiwagi, G. Orend and 2 more. Nature Medicine, 2009

709 citations recorded by the source corpus.

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.

Subfields: Immunology, Immunology and Allergy

View Paper: https://www.semanticscholar.org/paper/79b40f47cf3c20800b9f3c5ed4a760336fcf0df2

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In Immunology

1. L. Sorokin
2. S. Goldring
3. N. Itano
4. Pawared Ontong
5. C. Scanzello
6. Theerawut Chanmee
7. Ken-ichi Konno

Citations in the corpus

• The Role of Synovitis in Osteoarthritis pathogenesis (2012, background): “These include matrix components such as tenascin C [72,19], fibronectin isoforms [17,59], small molecular weight species of hyaluronic acid [6,91,105,106] and biglycan [9,23,80,90].”
• Fibroblasts: origins, definitions, and functions in health and disease (2021, background): “For instance, the ECM component tenascin-C can activate TLR4 signaling in synovial fibroblasts and induce pro-inflammatory cytokine production in the mouse model of rheumatoid arthritis (Midwood et al., 2009), whereas in the heart, DAMP signaling activates an inflammatory and profibrotic response by”
• Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment (2014, background): “induces cytokine synthesis in macrophages as an endogenous activator of TLR4 in arthritic joint disease [43].”
• Osteoarthritis: a disease of the joint as an organ. (2012, background): “These include matrix components such as tenascin C (91), fibronectin isoforms (27, 28), and fragments of hyaluronic acid (92).”
• Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis (2020, background): “Several endogenous TLR4-ligands such as the small heat shock protein crystalline, B8, or tenascin C are present in the synovial membrane, where they promote joint inflammation with a confirmed role for TLR4 in the pathogenesis of RA [319,320].”
• Extracellular matrix structure. (2016, background): “Other receptors for matricellular proteins are the calcium channel gabapentin receptor (α2δ-1) for TSPs and TLR4 for TN-C indicating involvement of these proteins in immune responses [238, 246, 247].”
• DAMPening Inflammation by Modulating TLR Signalling (2010, background): “Current strategies in clinical development for TLR blockade include (1) global blockade of individual TLR function using neutralizing antibodies, soluble TLR extracellular domains (ECDs), natural antagonists, and small molecule inhibitors, (2) inhibition of signalling pathways-activated downstream o”
• The impact of the extracellular matrix on inflammation (2010, background): “For example, tenascin C, which is normally expressed at low levels in healthy synovia but is upregulated in inflamed synovia, synovial fluid and cartilage from individuals with rheumatoid arthritis and corresponding mouse models, interacts with TLR4 on macrophages and synovial fibroblasts to induce ”
• The role of oxidative stress during inflammatory processes (2013, neutral): “, 2011), – Tenascin-C: TLR4 (Midwood et al., 2009) – Fibrinogen fragments: TLR4 (Millien et al.”