Tenascin-C aggravates autoimmune myocarditis via dendritic cell activation and Th17 cell differentiation.
BACKGROUND
Tenascin-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.


RESULTS
A 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.


CONCLUSIONS
Our 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.
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Tomoko
T
Machino-Ohtsuka
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Kazuko
K
Tajiri
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Taizo
T
Kimura
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Satoshi
S
Sakai
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Akira
A
Sato
Mie University Research Center for Matrix Biology and Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan (T.Y., K.I.Y.).
Toshimichi
T
Yoshida
Department of Cardiology, National Center of Global Health and Medicine, Tokyo, Japan (M.H.).
Michiaki
M
Hiroe
Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institution of Biomedical Innovation, Tsukuba, Japan (Y.Y.).
Yasuhiro
Y
Yasutomi
Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.M.O., K.T., T.K., S.S., A.S., K.A.).
Kazutaka
K
Aonuma
Mie University Research Center for Matrix Biology and Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan (T.Y., K.I.Y.).
Kyoko
K
Imanaka-Yoshida
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000276:immunology; D015398:Signal Transduction; D019063:Tenascin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016277:Ventricular Function, Left
D018836:Inflammation Mediators; D015850:Interleukin-6; C584019:Myh6 protein, mouse; D019063:Tenascin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C577686:interleukin-6, mouse; D018995:Myosin Heavy Chains
TLR4; Th17; dendritic cell; myocarditis; tenascin‐C