Innate Immune Interleukin-1 Receptor–Associated Kinase 4 Exacerbates Viral Myocarditis by Reducing CCR5+CD11b+ Monocyte Migration and Impairing Interferon Production

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 r...