Abstract
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.
Highlights
The plasminogen activation system, one of the major blood plasma proteolytic pathways, is best known for its role in dissolution of fibrin clots when they are no longer needed
The mannose 6-phosphate (M6P)/IGF2R surface expression increased when we differentiated the primary monocytes toward macrophages using macrophage colony-stimulating factor (M-CSF) (Fig. 1A) and this increase was recapitulated at the level of mRNA (Fig. 1B)
We concluded that the overexpression of M6P/IGF2R on differentiated macrophages was regulated at the level of transcription
Summary
The plasminogen activation system, one of the major blood plasma proteolytic pathways, is best known for its role in dissolution of fibrin clots when they are no longer needed. The active serine protease plasmin, a central player of the system, participates in many other physiological as well as pathological processes. Activation of plasminogen (Plg), a zymogen of plasmin, must be tightly balanced. Rampant plasmin activity contributes to tumor cell invasion,[1] on the other hand, plasmin deficiency may lead to impaired immune responses or neurodegeneration.[2,3,4] Recently, a novel role in the regulation of homeostasis has been ascribed to Plg; namely, Plg binds to the surface of apoptotic cells[5,6] and thereby induces their clearance by resident macrophages in the process of efferocytosis.[7] how phagocytes recognize Plg exposed on apoptotic cells has remained unknown
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