title: 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.
  
  
  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.affiliation: 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.).
authors.forename: Alan
authors.initials: A
authors.lastname: Valaperti
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Nishii
authors.forename: Youan
authors.initials: Y
authors.lastname: Liu
authors.forename: Kotaro
authors.initials: K
authors.lastname: Naito
authors.forename: Megan
authors.initials: M
authors.lastname: Chan
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Carsten
authors.initials: C
authors.lastname: Skurk
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: George A
authors.initials: GA
authors.lastname: Wells
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D039481:CD11b Antigen / Q000032:analysis*; D002465:Cell Movement / Q000502:physiology; D018946:Chemokine CCL5 / Q000172:deficiency / Q000502:physiology; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D019281:Dimerization; D060467:Disease Resistance; D029822:Enterovirus B, Human / Q000502:physiology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000503:physiopathology; D050835:Interferon Regulatory Factors / Q000737:chemistry / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D007372:Interferons / Q000096:biosynthesis*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D009205:Myocarditis / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D000081207:Primary Immunodeficiency Diseases; D011499:Protein Processing, Post-Translational; D011828:Radiation Chimera; D019713:Receptors, CCR5 / Q000032:analysis* / Q000172:deficiency / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014779:Virus Replication
chemical_list: D039481:CD11b Antigen; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D050835:Interferon Regulatory Factors; D019713:Receptors, CCR5; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; D007372:Interferons; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
keywords: cell movement; heart failure; interferons; macrophages; myocarditis