Myeloid EGFR deficiency accelerates recovery from Aki via macrophage efferocytosis and neutrophil apoptosis
Altered expression and activation of the Epidermal Growth Factor Receptor (EGFR) is implicated in acute and chronic kidney injury. In addition to expression in intrinsic kidney cells, EGFR is expressed in myeloid cells, which play important roles to promote both acute kidney injury and subsequent fibrosis. In murine ischemic acute kidney injury (AKI), myeloid deletion of EGFR promoted a proresolving, anti-inflammatory phenotype and increased efferocytotic capacity in macrophages, accelerated recovery in response to AKI and inhibited subsequent development of tubulointerstitial fibrosis. We found that selective EGFR expression and activation in neutrophils also accelerated recovery from ischemic kidney injury and reduced subsequent fibrosis. EGFR activation played an essential role in increasing the life span of neutrophils in the injured kidney, and deletion of EGFR expression either in all murine myeloid cells or selectively in neutrophils decreased kidney neutrophil Mcl-1 expression and promoted neutrophil apoptosis, which was accompanied by accelerated recovery from organ injury and reduced subsequent fibrosis. These studies identify previously undescribed coordinated and complementary roles for EGFR activation in neutrophils and macrophages to exacerbate kidney injury. Overall design: leukocytes were enriched with CD45 microbeads  from both EGFRf/f (WT) and CD11b-Cre: EGFRf/f (myeloid EGFR-/-) mice underwent ischemic injury for 1 and 3 days for single cell RNA-seq (scRNA-seq)