• Tomoko Machino-Ohtsuka, Kazuko Tajiri, Taizo Kimura, Satoshi Sakai, Akira Sato, Toshimichi Yoshida, Michiaki Hiroe, Yasuhiro Yasutomi, Kazutaka Aonuma, and Kyoko Imanaka-Yoshida.
• Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
• J Am Heart Assoc. 2014 Nov 5; 3 (6): e001052.

BackgroundTenascin-C (TN-C), an extracellular matrix glycoprotein, appears at several important steps of cardiac development in the embryo, but is sparse in the normal adult heart. TN-C re-expresses under pathological conditions including myocarditis, and is closely associated with tissue injury and inflammation in both experimental and clinical settings. However, the pathophysiological role of TN-C in the development of myocarditis is not clear. We examined how TN-C affects the initiation of experimental autoimmune myocarditis, immunologically.Methods And ResultsA model of experimental autoimmune myocarditis was established in BALB/c mice by immunization with murine α-myosin heavy chains. We found that TN-C knockout mice were protected from severe myocarditis compared to wild-type mice. TN-C induced synthesis of proinflammatory cytokines, including interleukin (IL)-6, in dendritic cells via activation of a Toll-like receptor 4, which led to T-helper (Th)17 cell differentiation and exacerbated the myocardial inflammation. In the transfer experiment, dendritic cells loaded with cardiac myosin peptide acquired the functional capacity to induce myocarditis when stimulated with TN-C; however, TN-C-stimulated dendritic cells generated from Toll-like receptor 4 knockout mice did not induce myocarditis in recipients.ConclusionsOur results demonstrated that TN-C aggravates autoimmune myocarditis by driving the dendritic cell activation and Th17 differentiation via Toll-like receptor 4. The blockade of Toll-like receptor 4-mediated signaling to inhibit the proinflammatory effects of TN-C could be a promising therapeutic strategy against autoimmune myocarditis.© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

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