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.
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.
Maekawa
Yuichiro
Y
Toronto General Hospital, University Health Network, Toronto, Ontario M5G2C4, Canada.
Mizue
Nobuo
N
Chan
Annie
A
Shi
Yu
Y
Liu
Youan
Y
Dawood
Steven
S
Chen
Manyin
M
Dawood
Fayez
F
de Couto
Geoffrey
G
Li
Guo Hua
GH
Suzuki
Nobutaka
N
Yeh
Wen-Chen
WC
Gramolini
Anthony
A
Medin
Jeffrey A
JA
Liu
Peter P
PP
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*
D053592:Interleukin-1 Receptor-Associated Kinases