Survival and Cardiac Remodeling after Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor Associated Kinase-4 (IRAK-4) Signaling: A Regulator of Bone Marrow-Derived Dendritic Cells

Background: The Innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor associated kinase-4 (IRAK-4), downstream to 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 the left ventricular (LV) remodeling following MI. Methods and Results: Experimental MI was created in IRAK-4-/- and wild-type (WT) mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks post-MI. IRAK-4-deficient mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less pro-inflammatory and Th1 cytokines 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 (DCs), inhibition of apoptosis and reduced fibrosis and nitric oxide production. Cardiac DCs in IRAK-4-/- mice were relatively immature or functionally naïve, as they demonstrated less cytokine and costimulatory molecule gene expression, whereas cardiac DCs in WT mice were mature and functional following MI. Furthermore, IRAK-4-/- DCs have less mobilization capacity. Transfer of WT-derived bone marrow DCs into IRAK-4-/- mice for functional dendritic cell reconstitution negated the survival advantage and reduced cardiac dilation observed with IRAK-4-/- mice at 28 days after MI. Conclusions: Deletion of IRAK-4 has favorable effects on survival and LV remodeling post myocardial infarction through modification of the host inflammatory process by blunting the detrimental bone marrow DCs mobilization after myocardial ischemia.