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RESEARCH HIGHLIGHTS RHEUMATOID ARTHRITIS Tenascin C: a candidate for chronic inflammation? After more than a decade of studying joint destruction after induction of during signal transduction) to block tenascin C, Kim Midwood and erosive arthritis—inflammatory cell FBG induction of IL-6. FBG also failed to colleagues have discovered a role for infiltration and synovial thickening induce cytokine synthesis in fibroblasts this extracellular matrix protein as an occurred, but tissue destruction and cell from Myd88–/– mice. Neutralizing endogenous ligand for Toll-like receptor death did not ensue. antibodies to TLR4 inhibited the (TLR) 4 that mediates persistent synovial Exogenous tenascin C induced tumor FBG-induced synthesis of TNF, IL-6 inflammation in arthritic joint disease. necrosis factor (TNF), interleukin and IL-8, and FBG could not induce these Tenascin C is normally only (IL)-6 and IL-8 in primary human cytokines in fibroblasts or macrophages expressed—transiently—in adult macrophages, and IL-6 in human from Tlr4–/– mice; furthermore FBG tissues in response to injury. However, fibroblasts. Tenascin C comprises several could not induce joint inflammation in in chronic inflammatory diseases, domains; the researchers established Tlr4–/–mice, indicating that FBG signals such as rheumatoid arthritis (RA), that only the ‘fibrinogen-like globe’ via TLR4. expression persists, particularly in the (FBG) domain was active in human The researchers plan to “…identify ways synovia, synovial fluid and cartilage. macrophages, synovial fibroblasts and to inhibit the proinflammatory action of This expression, together with the high an ex vivo model system of RA (synovial tenascin C in the hope that this may be homology of domains within tenascin C membranes from RA patients). Intra- useful in reducing chronic inflammation to other endogenous proinflammatory articular injection of FBG into wild-type in the joint”. molecules, prompted Midwood et al. mice induced joint inflammation. Katrin Legg to investigate this protein in the Midwood et al. then demonstrated that immune response. TLR signaling mediated tenascin-C- Original article Midwood, K. et al. Tenascin-C is an Acute inflammation was not induced cytokine production by using endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritis joint disease. Nat. sustained in mice lacking tenascin C. a dominant-negative form of MyD88 Med. 15, 774–780 (2009). Tnc–/– mice were also protected from (an adaptor protein recruited to TLRs NATURE REVIEWS | RHEUMATOLOGY VOLUME 5 | SEPTEMBER 2009 | 469 © 2009 Macmillan Publishers Limited. All rights reserved.

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