title: Survival and cardiac remodeling after myocardial infarction are critically dependent on the host innate immune interleukin-1 receptor-associated kinase-4 signaling: a regulator of bone marrow-derived dendritic cells.
abstract: BACKGROUND
  The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor-associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI.
  
  
  RESULTS
  Experimental MI was created in IRAK-4(-/-) and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4(-/-) mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-kappaB and c-Jun N-terminal kinase activation. IRAK-4(-/-) mice had fewer infiltrations of CD45+ leukocytes and CD11c+ dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4(-/-) mice were relatively immature or functionally naïve after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4(-/-) dendritic cells have less mobilization capacity. Transfer of wild type-derived bone marrow dendritic cells into IRAK-4(-/-) mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4(-/-) mice at 28 days after MI.
  
  
  CONCLUSIONS
  Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia.
authors.affiliation: Toronto General Hospital, University Health Network, Toronto, Ontario M5G2C4, Canada.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Mizue
authors.forename: Annie
authors.initials: A
authors.lastname: Chan
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.forename: Youan
authors.initials: Y
authors.lastname: Liu
authors.forename: Steven
authors.initials: S
authors.lastname: Dawood
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Fayez
authors.initials: F
authors.lastname: Dawood
authors.forename: Geoffrey
authors.initials: G
authors.lastname: de Couto
authors.forename: Guo Hua
authors.initials: GH
authors.lastname: Li
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Anthony
authors.initials: A
authors.lastname: Gramolini
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000502:physiology*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000276:immunology / Q000401:mortality / Q000503:physiopathology*; D009504:Neutrophils / Q000276:immunology; D016133:Polymerase Chain Reaction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases