Search

Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis , denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation. [Display omitted] Design of chimeric receptors for efferocytosis (CHEF) to enhance efferocytosis Boosting efferocytosis via CHEF attenuates multiple inflammatory insults in vivo Protein folding and misfolded protein degradation are rate-limiting steps in efferocytosis CHEF expression can improve outcomes in ongoing disease Chimeric receptors comprising an extracellular phosphatidylserine recognition domain and the signalling domain of a cytoplasmic adaptor protein boost clearance of apoptotic cells in damaged tissue and improve the disease outcome. [ABSTRACT FROM AUTHOR]