The Urokinase Plasminogen Activator Receptor Promotes Efferocytosis of Apoptotic Cells

Abstract

The urokinase receptor (uPAR), expressed on the surface of many cell types, coordinates plasmin-mediated cell surface proteolysis for matrix remodeling and promotes cell adhesion by acting as a binding protein for vitronectin. There is great clinical interest in uPAR in the cancer field as numerous reports have demonstrated that up-regulation of the uPA system is correlated with malignancy of various carcinomas. Using both stable cell lines overexpressing uPAR and transient gene transfer, here we provide evidence for a non-reported role of uPAR in the phagocytosis of apoptotic cells, a process that has recently been termed efferocytosis. When uPAR was expressed in human embryonic kidney cells, hamster melanoma cells, or breast cancer cells (BCCs), there was a robust enhancement in the efferocytosis of apoptotic cells. uPAR-expressing cells failed to stimulate engulfment of viable cells, suggesting that uPAR enhances recognition of one or more determinant on the surface of the apoptotic cell. uPAR-mediated engulfment was not inhibited by expression of mutant ␤5 integrin, nor was ␣v␤5 integrin-mediated engulfment modulated by cleavage of uPAR by phosphatidylinositol-specific phospholipase C. Further, we found that the more aggressive BCCs had a higher phagocytic capacity that correlated with uPAR expression and cleavage of membraneassociated uPAR in MDA-MB231 BCCs significantly impaired phagocytic activity. Because efferocytosis is critical for the resolution of inflammation and production of anti-inflammatory cytokines, overexpression of uPAR in tumor cells may promote a tolerogenic microenvironment that favors tumor progression.

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

“…Notably, the urokinase plasminogen activator receptor has recently been described as a novel engulfment receptor (20), although its prophagocytic role remains controversial (21). Moreover, Das and Plow (22) have described the histone 2B-dependent recruitment of plasminogen to PS-rich surfaces, and it has been shown that PAI impairs apoptotic cell removal (23).…”

Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus

“…phagocytic uptake of apoptotic cells, 55 including apoptotic neutrophils. 56 Briassouli et al also recently suggested that there is an interaction between the SLE-associated autoantigen Ro60…”

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

“…This uPAR-mediated efferocytosis required high molecular weight kininogen as a bridging molecule between phosphatidylserine (exposed on the apoptotic cell) and uPAR (on the phagocyte). In line with these results, there is another study reporting increased uptake of apoptotic T cells in uPAR overexpressing cancer cell lines [108]. Partly in contrast with these results, Park et al demonstrated increased macrophage efferocytosis of apoptotic neutrophils when uPAR was knocked-out, either in the neutrophil or the macrophage, but interestingly not when knocked-out in both cell types [109].…”

“…Since a defective clearance of dying cells is central in the SLE pathogenesis it is of interest to note that uPAR expression has been found to regulate efferocytosis [107][108][109][110] Briassouli et al found anti-SSA/Ro60 to up-regulate cardiocyte uPAR expression, and that this resulted in reduced efferocytosis and increased plasminogen activity [117]. Further, the augmentation of plasminogen activity resulted in transforming growth factor beta activation with a scarring phenotype of cardiac fibroblasts as a result [118].…”

“…Since a defective clearance of dying cells is central in the SLE pathogenesis it is of interest to note that uPAR expression has been found to regulate efferocytosis [107][108][109][110], i.e. the phagocytic uptake of dying cells.…”