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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.

circulation

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

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

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