Myeloid cell-specific β2-adrenergic receptor deletion improves early cardiac injury resolution via de-repression of Anxa1

<b>Rationale:</b> Myeloid cells, including neutrophils (Nu), monocytes (Mo) and macrophages (Mac), rapidly accumulate after ischemic cardiac injury where they play integral roles in inflammation and repair. β2-adrenergic receptor (β2AR) signaling regulates numerous facets of immune cell behavior, but its impact on myeloid cell-specific responses to acute cardiac injury is unclear. <b>Methods:</b> Myeloid cell-specific β2AR knockout (LB2) and control mice were subjected to myocardial infarction (MI) with or without prior transplantation with shRNA-modified bone marrow. The impact of myeloid cell-specific β2AR deletion, and mechanistic basis for the effect, were assessed via echocardiography, immunohistochemistry, flow cytometry, gene expression and efferocytosis analyses. <b>Results:</b> LB2 mice displayed better cardiac function and less fibrotic remodeling post-MI. Despite a similar initial influx of myeloid cell subtypes, by 4 days post-MI LB2 mice had significantly reduced Nu, concurrent with increased Nu-containing Mac, indicating an enhanced efferocytosis capacity. Indeed, the pro-efferocytotic protein annexin A1 (AnxA1) was elevated in several β2AR-deficient myeloid cell types following MI. Mechanistically, we found the expression of several miRs known to repress <i>Anxa1</i> expression were elevated in response to β2AR stimulation, an effect absent with β2AR deletion, and miR-374b-5p mimic in particular was sufficient to decrease <i>Anxa1</i> expression. Finally, lentivirus-encoded shRNA was used to induce knockdown of <i>Anxa1</i> expression in the bone marrow of LB2 mice prior to MI, which reduced Nu efferocytosis <i>in vitro</i> and prevented the ameliorative effects on cardiac fibrosis and function observed with LB2 mice following MI <i>in vivo</i>. <b>Conclusion:</b> Myeloid cell-specific β2AR deletion leads to loss of miR-374b-5p-mediated repression of AnxA1, which allows for enhanced efferocytosis-mediated Nu clearance, thereby limiting infarct expansion and improving post-injury cardiac function and fibrotic remodeling.