Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts

Wei Chen, Amit Saxena, Na Li, Jinyu Sun, Amit Gupta, Dong Wook Lee, Qi Tian, Marcin Dobaczewski, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Objective-Effective postinfarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, interleukin-1 receptor-associated kinase (IRAK)-M acts as a functional decoy preventing uncontrolled toll-like receptor/interleukin-1-mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the postinfarction inflammatory response and as a modulator of cardiac remodeling. Methods and Results-In wild-type mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared with wild-type animals, infarcted IRAK-M-/- mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M-/- animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M-/- infarcts showed increased infiltration with proinflammatory CD11b+/Ly6Chi monocytes; leukocytes harvested from IRAK-M-null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity. Conclusion-Endogenous IRAK-M attenuates adverse postinfarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.

Original languageEnglish (US)
Pages (from-to)2598-2608
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • Cardiac remodeling
  • Cytokines
  • Immune system
  • Macrophages
  • Metalloproteinases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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