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 language | English (US) |
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Pages (from-to) | 2598-2608 |
Number of pages | 11 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 32 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2012 |
Keywords
- Cardiac remodeling
- Cytokines
- Immune system
- Macrophages
- Metalloproteinases
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine