Innate Immune Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Exacerbates Viral Myocarditis by Reducing CCR5+CD11b+ Monocytes Migration and Impairing Interferon Production
Background—Viral myocarditis follows a fatal course in approximately 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 aim 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 (CVB3) into C57Bl/6 IRAK4 deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4-/- mice compared to their IRAK4+/+ littermates. Disease resistance of IRAK4-/- mice paralleled increased amounts of protective heart-infiltrating CCR5+ monocytes/macrophages and enhanced interferon (IFN)-α and IFN-γ production 2 days post infection (p.i.). 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 (IRF)5 homo-dimerization via reduced MDA5 degradation, and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral IFN-α and IFN-γ production, as well as CCR5+ cell recruitment, increased, while the overall pro-inflammatory response was drastically reduced in the absence of IRAK4.
Conclusions—Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of IFN production, and reduced mobilization of protective CCR5+ monocytes/macrophages to the heart. Combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.
- Received February 27, 2013.
- Revision received July 10, 2013.
- Accepted July 30, 2013.