doi: 10.1161/CIRCULATIONAHA.105.536433
(Circulation. 2005;112:2276-2285.)
© 2005 American Heart Association, Inc.
Heart Failure |
Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3–Induced Myocarditis and Influences Type I Interferon Production
From the Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, and Division of Cardiology, University Health Network, Toronto, Canada (K.F., G.C., Y.L., P.G., M.H., M.C., P.P.L.); Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto (W.-C.Y.), Toronto, Canada; and the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan (S.A.).
Correspondence to Peter P. Liu, MD, Heart and Stroke/Richard Lewar Centre of Excellence, NCSB11-1266, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca
Received January 18, 2005; revision received May 7, 2005; accepted June 17, 2005.
Background— Myeloid differentiation factor (MyD)-88 is a key adaptor protein that plays a major role in the innate immune pathway. How MyD88 may regulate host response in inflammatory heart disease is unknown.
Methods and Results— We found that the cardiac protein level of MyD88 was significantly increased in the hearts of wild-type mice after exposure to Coxsackievirus B3 (CVB3). MyD88–/– mice showed a dramatic higher survival rate (86%) in contrast to the low survival (35%) in the MyD88+/+ mice after CVB3 infection (P<0.0001). Pathological examination showed a significant decrease of cardiac and pancreatic inflammation in the MyD88–/– mice. Viral concentrations in the hearts were significantly decreased in the MyD88–/– mice. Cardiac mRNA levels for interleukin (IL)-1ß, tumor necrosis factor (TNF)-
, interferon (IFN)-
, and IL-18 were significantly decreased in the MyD88–/– mice. Similarly, serum levels of T-helper 1 cytokines were significantly decreased in the MyD88–/– mice. In contrast, cardiac protein levels of the activated interferon regulatory factor (IRF)-3 and IFN-ß were significantly increased in the MyD88–/– mice but not other usual upstream signals to IRF-3. The cardiac expression of coxsackie-adenoviral receptor and p56lck were also significantly decreased.
Conclusions— MyD88 appears to be a key contributor to cardiac inflammation, mediating cytokine production and T-helper-1/2 cytokine balance, increasing coxsackie-adenoviral receptor and p56lck expression and viral titers after CVB3 exposure. Absence of MyD88 confers host protection possibly through novel direct activation of IRF-3 and IFN-ß.
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