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.

• Keywords
• M6P/IGF2R, efferocytosis, macrophages, plasminogen, tissue homeostasis,
• MeSH
• Cell Differentiation drug effects   MeSH
• Phagocytosis drug effects   MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Gene Knockout Techniques MeSH
• Jurkat Cells MeSH
• Humans MeSH
• Macrophages cytology   drug effects   metabolism   MeSH
• Mice MeSH
• Plasminogen pharmacology   MeSH
• Receptor, IGF Type 2 metabolism   MeSH
• THP-1 Cells MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Plasminogen MeSH
• Receptor, IGF Type 2 MeSH
• Tumor Necrosis Factor-alpha MeSH