Midwood, K. et al. TenascinC is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritis joint disease. Nat. Med. 15, 774–780 (2009).

After more than a decade of studying tenascin C, Kim Midwood and colleagues have discovered a role for this extracellular matrix protein as an endogenous ligand for Toll-like receptor (TLR) 4 that mediates persistent synovial inflammation in arthritic joint disease.

Tenascin C is normally only expressed—transiently—in adult tissues in response to injury. However, in chronic inflammatory diseases, such as rheumatoid arthritis (RA), expression persists, particularly in the synovia, synovial fluid and cartilage. This expression, together with the high homology of domains within tenascin C to other endogenous proinflammatory molecules, prompted Midwood et al. to investigate this protein in the immune response.

Acute inflammation was not sustained in mice lacking tenascin C. Tnc−/− mice were also protected from joint destruction after induction of erosive arthritis—inflammatory cell infiltration and synovial thickening occurred, but tissue destruction and cell death did not ensue.

Exogenous tenascin C induced tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 in primary human macrophages, and IL-6 in human fibroblasts. Tenascin C comprises several domains; the researchers established that only the 'fibrinogen-like globe' (FBG) domain was active in human macrophages, synovial fibroblasts and an ex vivo model system of RA (synovial membranes from RA patients). Intra-articular injection of FBG into wild-type mice induced joint inflammation.

Midwood et al. then demonstrated that TLR signaling mediated tenascin-C-induced cytokine production by using a dominant-negative form of MyD88 (an adaptor protein recruited to TLRs during signal transduction) to block FBG induction of IL-6. FBG also failed to induce cytokine synthesis in fibroblasts from Myd88−/− mice. Neutralizing antibodies to TLR4 inhibited the FBG-induced synthesis of TNF, IL-6 and IL-8, and FBG could not induce these cytokines in fibroblasts or macrophages from Tlr4−/− mice; furthermore FBG could not induce joint inflammation in Tlr4−/− mice, indicating that FBG signals via TLR4.

The researchers plan to “...identify ways to inhibit the proinflammatory action of tenascin C in the hope that this may be useful in reducing chronic inflammation in the joint”.