Editors' ChoiceInflammation

A Tenacious Hold on TLR4

Science Signaling  21 Jul 2009:
Vol. 2, Issue 80, pp. ec241
DOI: 10.1126/scisignal.280ec241

Rheumatoid arthritis is a chronic inflammatory disease that can progress to joint and bone destruction. Inhibitors against Toll-like receptor 4 (TLR4) have shown promise in alleviating symptoms of rheumatoid arthritis in clinical trials; however, the endogenous ligands that activate TLR4 during this condition were not known. Because the abundance of the extracellular matrix glycoprotein tenascin-C is increased in synovia, synovial fluid, and cartilage of individuals with rheumatoid arthritis, and because tenascin-C contains domains that resemble other TLR4 ligands, Midwood et al. wondered whether tenascin-C was a ligand for TLR4. In wild-type mice, injection of methylated bovine serum albumin (mBSA) into intra-articular spaces to cause erosive arthritis led to chondrocyte death and cartilage and bone erosion. Tnc–/– mice showed signs of inflammation (such as cell infiltration) shortly after mBSA injection; however, inflammation was not sustained and did not progress to joint destruction. Tenascin-C treatment of primary human macrophages and synovial fibroblasts induced production of inflammatory cytokines such as tumor necrosis factor–α (TNF-α), interleukin-6 (IL-6), and IL-8. More specifically, the fibrinogen-like globe (FBG) domain of tenascin-C induced TNF-α production in human macrophages and, when injected intra-articularly into wild-type mice, caused joint inflammation (as measured by inflammatory cell infiltration and synovitis), loss of cartilage proteoglycan, and chondrocyte death. Induction of production of IL-6 and TNF-α by the FBG domain required TLR4 and its downstream adapter protein, myeloid differentiation factor 88 (MyD88). Because the abundance of tenascin-C is increased during acute inflammation and remains elevated during chronic inflammation, the authors propose that tenascin-C drives the persistent inflammation characteristic of rheumatoid arthritis.

K. Midwood, S. Sacre, A. M. Piccinini, J. Inglis, A. Trebaul, E. Chan, S. Drexler, N. Sofat, M. Kashiwagi, G. Orend, F. Brennan, B. Foxwell, 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). [PubMed]

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