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

نویسندگان

  • Wei Chen
  • Amit Saxena
  • Na Li
  • Jinyu Sun
  • Amit Gupta
  • Dong-Wook Lee
  • Qi Tian
  • Marcin Dobaczewski
  • Nikolaos G Frangogiannis
چکیده

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+/Ly6C(hi) 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. CONCLUSIONS Endogenous IRAK-M attenuates adverse postinfarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function.

Regulatory T cells (Tregs) play a pivotal role in suppressing immune responses regulating behavior and gene expression in effector T cells, macrophages, and dendritic cells. Tregs infiltrate the infarcted myocardium; however, their role the inflammatory and reparative response after myocardial infarction remains poorly understood. We used FoxP3(EGFP) reporter mice to study Treg trafficking in t...

متن کامل

SMAD4 is required for development of maximal endotoxin tolerance.

Initial exposure of monocytes/macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Molecular mechanisms responsible for endotoxin tolerance are not well defined. We and others have shown that IL-1R-associated kinase (IRAK)-M and SHIP-1 proteins, negative regulators of TLR4 signaling, increase in tolerized cells. TGF-beta1, an anti-infl...

متن کامل

IRAK-M Regulates Chromatin Remodeling in Lung Macrophages during Experimental Sepsis

Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis. Pulmonary macrophages (PM) recovered from t...

متن کامل

Inhibition of interleukin-12 p40 transcription and NF-kappaB activation by nitric oxide in murine macrophages and dendritic cells.

Nitric oxide (NO), an important effector molecule of the innate immune system, can also regulate adaptive immunity. In this study, the molecular effects of NO on the toll-like receptor signaling pathway were determined using interleukin-12 (IL-12) as an immunologically relevant target gene. The principal conclusion of these experiments is that NO inhibits IL-1 receptor-associated kinase (IRAK) ...

متن کامل

Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocard...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 32 11  شماره 

صفحات  -

تاریخ انتشار 2012