PS externalization: from corpse clearance to drug delivery

Abstract

Phosphatidylserine (PS) externalization on the plasma membrane of aging red blood cells and on apoptotic cell corpses serves as a common recognition signal for macrophages. 1 Perturbation of phospholipid asymmetry and rapid redistribution of PS also occurs in platelets and provides a procoagulant surface that promotes blood clotting. 2 In addition, several recent studies have revealed novel roles for altered plasma membrane phospholipid distribution in nonapoptotic cells. The aim of the present discourse is to highlight these emerging roles for PS externalization, and some of the putative therapeutic implications thereof. PS signaling is required for programmed cell clearancePhospholipid asymmetry is a common feature of all eukaryotic membranes. Moreover, mitotic and quiescent cells invest considerable amounts of energy to generate and maintain membrane lipid sidedness. Loss of phospholipid asymmetry and the concomitant externalization of PS can be readily monitored by the use of fluorescence-conjugated annexin V, an endogenous protein that specifically binds to PS, and this process has been well studied in platelets. Thus, when platelets are activated by agonists, such as thrombin and collagen, PS is rapidly brought to the surface of the cell. Exposed PS then catalyzes the assembly of proteins of the coagulation system, leading to a conversion of soluble fibrinogen into an insoluble fibrin clot. 2 The pivotal role of PS externalization is illustrated in Scott syndrome, a bleeding disorder characterized by an impaired Ca 2 þ -induced phospholipid scrambling, and hence an inability of platelets to promote blood coagulation. 2 Apoptotic cells are also procoagulant, and annexin V can completely abolish the procoagulant activity, suggesting that this effect is PS-dependent. 3 More recent findings suggest that annexin V-induced internalization of tissue factor (TF), the initiator of blood coagulation, may also contribute to the anticoagulant functions of annexin V (discussed below).The ability of PS to act as a signal for in vivo recognition and clearance of effete cells was demonstrated 20 years ago in studies of red blood cells. 4 Subsequent studies by Fadok et al. 5 showed that PS externalization also can trigger specific recognition and removal of apoptotic cells, and the exposition of PS was soon found to be a common, if not universal, event during apoptosis. 6 More recent studies have shown that PS externalization is, in fact, essential for corpse clearance by macrophages and nonprofessional phagocytes (fibroblasts). 1 Moreover, our studies have indicated that the generation of oxidized PS species (PS-OX) is an integral part of the apoptosis program. 7 Externalization of PS-OX on the cell surface potentiates macrophage engulfment of apoptotic cells, and could also serve to promote the binding of so-called bridging molecules (serum proteins) to apoptotic cell corpses. 8 Interestingly, deletion in mice of the PS-binding bridging molecule, milk fat globule epidermal growth factor 8 (MFG-E8) (also known as lactadhe...

Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor–Positive Microvesicles

“…Our data showed no significant changes in Under these conditions, a low level of cellular PS exposure was seen in the current ( Figure 1A) and previous studies 25 which could play a role in generation of PS-positive MVs by these cells. 38,39 In contrast, cholesterol enrichment caused a majority of the THP-1 monocytes to promptly display strong staining for PS on their surface by 2 hours ( Figure 1A and supplemental Figure III), and to gradually shrink over time, as shown by a downward shift in forward scatter ( Figure 1A). Because cell-surface exposure of PS not only induces procoagulant responses 5 but may also indicate early-stage apoptosis, 5,40 we examined a definitive marker of late-stage apoptosis, namely DNA fragmentation by TUNEL.…”

Epidermal Growth Factor-Like Domain Repeat of Stabilin-2 Recognizes Phosphatidylserine during Cell Corpse Clearance

“…Although PS is an important flag molecule for phagocytosis, the externalization of PS also occurs in nonapoptotic cells during various cellular processes, including platelet activation, cell fusion during myotube formation, syncytiotrophoblast formation, platelet release from progenitor cells, immunoglobulin E-dependent stimulation of mast cells, T-cell migration, and the formation of tumor vasculature (7,26,30). Furthermore, a recent study reported that inhibition of PS recognition heightens the immunogenicity of irradiated lymphoma cells (4).…”

Integration of cytokine biology and lipid metabolism in stroke

“…The PS relocation also causes flipping of SM from outer to inner leaflet and hydrolysis by a cytosolic SMase (66)(67)(68) to generate ceramide with subsequent activation of death cascade mechanisms.…”