Loss of Myeloid Cell-Specific β2-Adrenergic Receptor Expression Ameliorates Cardiac Function and Remodeling after Acute Ischemia

Abstract

Myeloid cells, including neutrophils, monocytes and macrophages, accumulate quickly after ischemic injury in the heart where they play integral roles in the regulation of inflammation and repair. We previously reported that deletion of {beta}2-adrenergic receptor ({beta}2AR) in all cells of hematopoietic origin resulted in generalized disruption of immune cell responsiveness to injury, but with unknown impact on myeloid cells specifically. To investigate this, we crossed floxed {beta}2AR (F/F) mice with myeloid cell-expressing Cre (LysM-Cre) mice to generate myeloid cell-specific {beta}2AR knockout mice (LB2) and subjected them to myocardial infarction (MI). Via echocardiography and immunohistochemical analyses, LB2 mice displayed better cardiac function and less fibrotic remodeling after MI than the control lines. Despite similar accumulation of myeloid cell subsets in the heart at 1-day post-MI, LB2 mice displayed reduced numbers of Nu by 4 days post-MI, suggesting LB2 hearts have enhanced capacity for Nu efferocytosis. Indeed, bone marrow-derived macrophage (BMDM)-mediated efferocytosis of Nu was enhanced in LB2-versus F/F-derived cells in vitro. Mechanistically, several pro-efferocytosis-related genes were increased in LB2 myeloid cells, with annexin A1 (Anxa1) in particular elevated in several myeloid cell types following MI. Accordingly, shRNA-mediated knockdown of Anxa1 in LB2 bone marrow prior to transplantation into irradiated LB2 mice reduced Mac-induced Nu efferocytosis in vitro and prevented the ameliorative effects of myeloid cell-specific {beta}2AR deletion on cardiac function and fibrosis following MI in vivo. Altogether, our data reveal a previously unrecognized role for {beta}2AR in the regulation of myeloid cell-dependent efferocytosis in the heart following injury.