The healthy heart comprises immune cells, mainly macrophages of differing class and origin. While these myeloid cells remain an area of continuous investigation, we have come to appreciate that a subset of tissue residing macrophages (TRMs) seed the heart during development and are maintained through self-renewal. Further, TRMs continue to be linked to the maintenance of cardiac homeostasis, for instance, through facilitating crosstalk with other cardiac cells, and participating in immunosurveillance. In the case of injury however, such as a myocardial infarction (MI), TRMs are largely replaced by circulating and recruited myeloid cells. Post-infarct macrophages (mf) are greater in number and class, and functionally, debris clearance and initiation of cardiac repair mechanisms becomes their utmost priority to limit the severity of heart failure (HF). Given these significant roles, it has become critical to understand how cardiac myeloid cells are regulated, and what mechanisms contribute to their known functions both at steady-state and following injury. Epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor known to govern cell function through myriad processes. Although historically studied as an oncogene, EGFR has been shown to regulate cardiac physiology, and notably mf activation, survival and function. However, it is currently unknown whether EGFR influences myeloid homeostasis within the heart. Thus, we have generated myeloid-specific EGFR knockout mice (EGFRmylKO) by crossing floxed EGFR (EGFR ) with LysM Cre mice and performed comparative analyses between the lines at baseline and following injury. In response to MI, EGFRmylKO mice exhibit altered inflammatory responses, resulting in aggravated cardiac dysfunction, exacerbated hypertrophic remodeling, and limited angiogenic repair. These functional and structural outcomes are preceded by a disruption in the post-injury myeloid cell infiltration continuum that favors adequate repair, resulting in decreased transcripts of reparative factors including IL-10. Additionally, EGFRmylKO mouse hearts show modest signs of stress at baseline, in the absence of injury, including cardiomyocyte hypertrophy with an associated increase in expression of signature fetal gene transcripts. Whole transcriptome analysis of cardiac resident myeloid (Cd11b ) cells by RNASeq revealed over 700 differentially expressed genes that were significantly altered between EGFRmylKO and EGFR control mice. Among these are IGFBP family members 5 and 7, each known to regulate IGF availability, which itself has been recently shown to influence cardiac hypertrophy. In sum, our results reveal that myeloid cell-expressed EGFR plays previously unknown roles in the regulation of the cardiac homeostasis baseline as well as the chronic remodeling response to ischemic injury.
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