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

If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ+CD39+CD73+ Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.

• Keywords
• adenosine, chronic inflammation, macrophage polarization, macrophage-T cell interaction, methotrexate, purine metabolism, rheumatoid arthritis,
• MeSH
• Adenosine immunology   MeSH
• Cell Differentiation * MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor pharmacology   MeSH
• Macrophage Colony-Stimulating Factor pharmacology   MeSH
• Immunosuppressive Agents administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Macrophages immunology   metabolism   MeSH
• Methotrexate administration & dosage   therapeutic use   MeSH
• Disease Models, Animal MeSH
• Monocytes drug effects   MeSH
• Mice MeSH
• Cell Proliferation MeSH
• Purines metabolism   MeSH
• Arthritis, Rheumatoid drug therapy   immunology   MeSH
• Synovial Fluid cytology   immunology   MeSH
• Inflammation drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenosine MeSH
• Granulocyte-Macrophage Colony-Stimulating Factor MeSH
• Macrophage Colony-Stimulating Factor MeSH
• Immunosuppressive Agents MeSH
• Methotrexate MeSH
• Purines MeSH