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

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.

Role of innate and adaptive immune mechanisms in cardiac injury and repair

“…The expression of RLRs is greatly enhanced in response to type I IFN stimulation or virus infection. MDA5 is the best characterized receptor in this family, with loss in cardiomyocytes leading to uncontrolled viral replication and rapid death, while over-expression resulting in protection from lethal myocarditis 48–50 . One important issue which has only been partially addressed thus far is the delineation of cell-types specific roles for PRRs.…”

CCR5del32 genotype in human enteroviral cardiomyopathy leads to spontaneous virus clearance and improved outcome compared to wildtype CCR5

“…CCR5 is crucial for the antiviral immune response and closely regulated by IRAK4, which suppresses several antiviral key mechanisms [31]. Loss of IRAK 4 function in knockout mice increases the number of CCR5 on monocytes and leads to the elimination of enterovirus and better survival of enterovirus-infected mice.…”

“…Loss of IRAK 4 function in knockout mice increases the number of CCR5 on monocytes and leads to the elimination of enterovirus and better survival of enterovirus-infected mice. In this mouse model, the infiltration of CCR5 + monocytes/macrophages is beneficial for virus elimination and therefore shows controversial results to our study of humans [31]. …”

Chemokine receptor patterns and right heart failure in mechanical circulatory support

“…Valaperti et al reported that interleukin-1 receptor-associated kinase 4 (IRAK4), a major innate immunity signal transducer, worsens Coxsackievirus B3 induced viral myocarditis in mice by reducing early recruitment of protective CCR5+ monocytes/macrophages to the heart (19). Mortality and viral proliferation rates were increased in CCR5 knockout mice, highlighting the importance of CCR5 mediated effects on cardioprotection and antiviral defense.…”