Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor-Associated Kinase-4 Signaling

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-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.

Innate Immune Interleukin-1 Receptor–Associated Kinase 4 Exacerbates Viral Myocarditis by Reducing CCR5 + CD11b + Monocyte Migration and Impairing Interferon Production

“…6,16,17 In fact, IRAK4 contributes to TLR2-and TLR4-triggered inflammation in a mouse model of myocardial infarction. 18,19 In the present study, we demonstrate that loss of IRAK4 protects from myocarditis. Despite drastic reduction of TLR-mediated inflammation in the absence of IRAK4, antiviral pathways were markedly activated.…”

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

“…Reperfusion is associated with additional tissue damages, called lethal reperfusion injuries (6,7). There is increasing evidence advocating the implication of innate immune cells, especially dendritic cells (DCs), in myocardial I/R injuries (8)(9)(10). DCs express a large array of DAMP receptors, particularly P2Rs that are crucial factors of the DAMP-mediated immune response (11,12).…”

“…Besides their ability to activate T cells, DCs have been shown to orchestrate both innate and adaptive immune responses in the presence of danger signals (14,15). Some studies highlighted the important and intricate role of DCs in myocardial post-I/R injuries through the control of immune cell homeostasis (9,16). The authors suggested that DCs might be either beneficial or deleterious to organ functions according to the signaling pathways involved.…”

Systematic Characterization of Myocardial Inflammation, Repair, and Remodeling in a Mouse Model of Reperfused Myocardial Infarction

“…With the development of genetically targeted animals, mouse models of myocardial infarction have become valuable tools for dissecting the cellular and molecular pathways involved in cardiac remodeling (Jones and Lefer 2000;Hoit 2001;Maekawa et al 2009;Schellings et al 2009). Investigators have used a variety of methodological approaches, such as echocardiography (Pollick et al 1995;Takagawa et al 2007;Zhang et al 2007;Scherrer-Crosbie and Thibault 2008), quantitative morphometry (Huebener et al 2008), invasive hemodynamic monitoring (ScherrerCrosbie et al 2001) and magnetic resonance imaging (Nahrendorf et al 2008), to quantitatively assess remodelingassociated parameters and to study the role of specific molecular pathways in chamber dilation, hypertrophy, and systolic and diastolic dysfunction following myocardial infarction.…”