The Presumptive Phosphatidylserine Receptor Is Dispensable for Innate Anti-inflammatory Recognition and Clearance of Apoptotic Cells

Abstract

The role of the presumptive phosphatidylserine receptor (PSR) in the recognition and engulfment of apoptotic cells, and the antiinflammatory response they exert, has been of great interest. Genetic deficiency of PSR in the mouse is lethal perinatally, and results to date have been ambiguous with regard to the phagocytic and inflammatory phenotypes associated with that deficiency. Recently, we found that the specific functional recognition of apoptotic cells is a ubiquitous property of virtually all cell types, including mouse embryo fibroblasts, and reflects an innate immunity that discriminates live from effete cells. Physiological cell death is a process whose purpose is the elimination of functionally inappropriate cells in a manner that does not elicit inflammation. The ability of apoptotic corpses to be cleared in a noninflammatory manner by phagocytes is a consequence of their specific expression of determinants for recognition and modulation of pro-inflammatory responses. The acquisition of these apoptotic determinants is a gain-of-function common to all physiological cell deaths, without regard to suicidal stimulus, and conserved widely across species (1, 2).Numerous cellular alterations associated with apoptotic cell death have been described, including plasma membrane reorganization associated with blebbing (3), shrinkage, and the loss of membrane phospholipid asymmetry (4, 5). In particular, phosphatidylserine (PS), 4 an anionic phospholipid normally cloistered in the inner leaflet of the plasma membrane, is externalized during physiological cell death (5). It still remains to be determined what specific molecular events are responsible for the recognition of the effete cell.The view that externalized PS serves as a ligand for macrophage recognition of apoptotic cells followed from studies demonstrating that similar changes target aged erythrocytes for clearance (6, 7) and gained support from observations that phospho-L-serine and PS vesicles could inhibit partially the interaction of dying nucleated cells with macrophages (5,8,9).A presumptive cell surface PS-specific receptor (PSR) was identified molecularly following a screen for monoclonal antibodies whose binding to human macrophages was inhibited by PS-containing liposomes (10). The product of that screen, mAb 217, bound to cell surface determinants on macrophages and other cell types, notably excluding lymphoid cells. Significantly, mAb 217 triggered macrophages to release the anti-inflammatory cytokine TGF␤, further suggesting that mAb 217 engaged an apoptotic-like recognition mechanism (10).Controversy regarding this presumptive receptor arose, however, when PSR was observed to localize to the nucleus in mammalian cells (11) as well as in Hydra (12). The role of PSR has been further clouded by the disparate results of three groups of investigators who independently generated mice with targeted disruptions of the PSR locus (13-15). While homozygous PSR disruptions result in perinatal lethality in each case, different effects on the phagocytosi...

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

“…5 However, recent studies suggest considerable ambiguity regarding the localization of PSR on the cell surface 29 and whether it is crucial for the clearance of apoptotic cells. 30,31 The results of previous studies have demonstrated that CD14 and CD36 are involved in the phagocytosis of apoptotic cells as membrane receptors in HMDMs. However, CD14 appears unlikely to bind preferentially to apoptotic-cell-associated PS, and does not function as a PS-receptor on HMDMs.…”

Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair

“…In conceiving the strategy, several criteria guided us: the use of natural, well-defined and safe materials; the treatment should be minimally invasive; and the principles underlying the strategy to resolve inflammation should mimic the anti-inflammatory effects of apoptotic cell clearance by macrophages (16).…”

Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1

“…Jmjd6 was first thought to be a cell-surface receptor responsible for the recognition and phagocytosis of apoptotic cells (11). However, various following studies showed that Jmjd6 is localized in the nucleus (12)(13)(14)(15)(16) and is not involved in apoptotic cell clearance (17). Subsequently, a function as a histone arginine demethylase was identified (18) and a recent publication suggests that Jmjd6 regulates splicing by hydroxylating the splicing factor U2AF65 (19).…”