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

Yuichiro Maekawa, Nobuo Mizue, Annie Chan, Yu Shi, Youan Liu, Steven Dawood, Manyin Chen, Fayez Dawood, Geoffrey De Couto, Guo Hua Li, Nobutaka Suzuki, Wen Chen Yeh, Anthony Gramolini, Jeffrey A. Medin, Peter P. Liu

研究成果: Article査読

59 被引用数 (Scopus)

抄録

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-κB 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.

本文言語English
ページ(範囲)1401-1414
ページ数14
ジャーナルCirculation
120
14
DOI
出版ステータスPublished - 2009 10月
外部発表はい

ASJC Scopus subject areas

  • 循環器および心血管医学
  • 生理学(医学)

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