Alan Valaperti1, Mototsugu Nishii, Youan Liu, Kotaro Naito, Megan Chan, Liyong Zhang, Carsten Skurk, Heinz-Peter Schultheiss, George A Wells, Urs Eriksson, Peter P Liu. 1. Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada (A.V., M.N., Y.L., K.N., M.C., L.Z., P.P.L.); University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada (L.Z., G.A.W., P.P.L.); Department of Cardiology and Pneumology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany (C.S., H.S.); and Division of Cardioimmunology, Cardiovascular Research, Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Zurich, and Department of Medicine, GZO-Zurich Regional Health Centre, Wetzikon, Switzerland (U.E.).
Abstract
BACKGROUND: Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS: Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.
BACKGROUND:Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS:Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.
Authors: Aditi Nayak; Colin Neill; Robert L Kormos; Luigi Lagazzi; Indrani Halder; Charles McTiernan; Jennifer Larsen; Ana Inashvili; Jeffrey Teuteberg; Timothy N Bachman; Karen Hanley-Yanez; Dennis M McNamara; Marc A Simon Journal: J Heart Lung Transplant Date: 2016-12-23 Impact factor: 10.247
Authors: Kory J Lavine; Alexander R Pinto; Slava Epelman; Benjamin J Kopecky; Xavier Clemente-Casares; James Godwin; Nadia Rosenthal; Jason C Kovacic Journal: J Am Coll Cardiol Date: 2018-10-30 Impact factor: 24.094