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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. Circulation 2009 Oct 06;120(14):1401-14

Date

09/23/2009

Pubmed ID

19770394

DOI

10.1161/CIRCULATIONAHA.109.865956

Scopus ID

2-s2.0-70349750287   57 Citations

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.

METHODS AND 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.

Author List

Maekawa Y, Mizue N, Chan A, Shi Y, Liu Y, Dawood S, Chen M, Dawood F, de Couto G, Li GH, Suzuki N, Yeh WC, Gramolini A, Medin JA, Liu PP

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
Bone Marrow Cells
Crosses, Genetic
Dendritic Cells
Disease Models, Animal
Gene Deletion
Interleukin-1 Receptor-Associated Kinases
Macrophages
Mice
Mice, Knockout
Myocardial Infarction
Neutrophils
Polymerase Chain Reaction
Survival Rate
T-Lymphocytes
Ventricular Remodeling