Phosphatidylserine exposure in B lymphocytes: a role for lipid packing

Abstract

Plasma membrane lipids are usually distributed asymmetrically, with phosphatidylserine (PS) confined to the inner leaflet. PS exposure at the outer leaflet occurs early in apoptosis, but it is also constitutive on some nonapoptotic cell populations where it plays a role in cell signaling. How PS is transported ("flopped") to the cell surface is unknown. Contrary to previous reports that normal murine B lymphocytes lack lipid asymmetry, we show that PS is normally restricted to the inner leaflet of these cells. PS exposure on normal B cells did, however, occur spontaneously ex vivo. Consistent with the hypothesis that loss of PS asymmetry is regulated by CD45, PS is constitutively exposed on viable, CD45-deficient B cells. We show that calcium-stimulated PS exposure in B cells is strain variable, ABCA1 independent, and both preceded by and dependent on a decrease in lipid packing. This decrease in lipid packing is concomitant with cell shrinkage and consequent membrane distortion, both of which are potently inhibited by blockers of volumeregulatory K ؉ and Cl ؊ ion channels. Thus, changes in plasma membrane organization precede PS translocation. The data suggest a model in which PS redistribution may occur by a translocaseindependent mechanism at energetically favorable sites of membrane perturbation where lipid packing is decreased. (Blood.

Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm

“…14 On the other hand, PS is also detectable on the surfaces of membraneenclosed nuclei that are released from maturing erythroblasts; 30 and the release of these effete nuclei has been shown to involve a vesicle-mediated membrane fusion process. 31 Moreover, Ca 2 þ -stimulated PS exposure on murine B cells, which varies from strain to strain, has been shown to depend on cell shrinkage, 32 consistent with the findings summarized in Figure 8e. Whether cell shrinkage and/or membrane fusion, as opposed to scramblase activation, also plays a similar role in the currently unexplained appearance of PS on the surface of activated T lymphocytes 33 and on tumor exosomes 34 remains to be determined.…”

NADPH Oxidase-dependent Generation of Lysophosphatidylserine Enhances Clearance of Activated and Dying Neutrophils via G2A

“…Additionally, we noted that peritoneal neutrophils, although rarely exhibiting apoptotic nuclear features ( fig. 4A), frequently exposed PS (Annexin Vϩ and PIϪ; data not shown) confirming our own and others work demonstrating PS exposure on activated cells (53,54). Given these observations, we hypothesized that PS-exposed, activated neutrophils might be recognized similarly to apoptotic cells, and that lyso-PS production might enhance their optimal engulfment via G2A-mediated signaling.…”

“…Whether neutrophils exposing PS and generating lyso-PS in vivo are truly "eaten alive" or are beginning to undergo early apoptosis is at this point unclear and there is likely a continuum between PS exposure during activation and the appearance of other markers signifying cell death (59). We and others have previously published that PS exposure occurs on activated cells including neutrophils (53,54), and that PS on living cells can act as an "eat me" signal in mammalian systems (14) and possibly in Caenorhabditis elegans (60). In addition, this possibility may also explain the findings of Lagasse and Weissman (52) who demonstrated that activated neutrophils overexpressing Bcl-2, which were devoid of classic features of apoptosis (e.g.…”

Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

“…Apoptosis induces extracellular exposure of PS, whereupon immune scavenger cells bearing PS-specific receptors can recognize and remove the dying cells (1). This seemingly simple paradigm is complicated by the fact that extracellular PS exposure is not just a hallmark of cell death but is also functionally relevant during the activation of various immune cells, including T cells (3)(4)(5)(6)(7). Moreover, there exists a wide array of structurally diverse PS receptors, the expression of which is not strictly limited to immune cells capable of phagocytosis (8,9).…”