The mannose 6‐phosphate/insulin‐like growth factor 2 receptor mediates plasminogen‐induced efferocytosis

The plasminogen system is harnessed in a wide variety of physiological processes, such as fibrinolysis, cell migration, or efferocytosis; and accordingly, it is essential upon inflammation, tissue remodeling, wound healing, and for homeostatic maintenance in general. Previously, we identified a plasminogen receptor in the mannose 6‐phosphate/insulin‐like growth factor 2 receptor (M6P/IGF2R, CD222). Here, we demonstrate by means of genetic knockdown, knockout, and rescue approaches combined with functional studies that M6P/IGF2R is up‐regulated on the surface of macrophages, recognizes plasminogen exposed on the surface of apoptotic cells, and mediates plasminogen‐induced efferocytosis. The level of uptake of plasminogen‐coated apoptotic cells inversely correlates with the TNF‐α production by phagocytes indicating tissue clearance without inflammation by this mechanism. Our results reveal an up‐to‐now undetermined function of M6P/IGF2R in clearance of apoptotic cells, which is crucial for tissue homeostasis.