Phospholipid signaling from apoptotic cells

National Jewish Health, Denver CO

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Abstract

Following inflammation, apoptosis of unnecessary and damaged cells is a fundamental process of tissue restoration and repair. Engulfment and recycling of apoptotic cells by either professional or non-professional phagocytes results in their removal before noxious intracellular contents are dispersed, and actively suppresses inflammation. Indeed, defects in engulfment are linked to autoimmunity and over-exuberant inflammation. Increasing evidence suggests that phospholipids (PLs) of apoptosing cells serve as important signals for the recruitment, recognition and non-phlogistic engulfment by phagocytes. Unlike most other mediators, PLs are immediately available, but either latent (e.g phosphatidylserine (GPSer) which must be externalized), or can be "economically" modified to effectively signal the cell's demise. PL modification by oxidants, almost always present in apoptosis, and/or by remodeling phospholipases (PLA2s) is hypothesized to generate signaling PLs. Using sensitive mass spectrometry techniques, leading candidates for the attraction of phagocytes are proposed to be released lyso-phosphatidylcholine (lyso-GPCho), platelet activating factor (PAF), and lyso-GPSer species as well. The near-universal appearance of GPSer species in the plasma membrane outer leaflet results from inactivation of an aminophospholipid translocase (APLT) and activated PL flip-flop, and while GPSer is required for recognition, it is insufficient to drive phagocyte engulfment. Species of GPSer have not been defined and there is evidence that modification by oxidants is critical to the process. Preliminary data shows that both sn-2 and sn-1 lyso-GPSer are produced during apoptosis. Mounting data support the hypothesis that lyso-PLs signal for calcium flux, and as such, are hypothesized to drive PL flip-flop and inhibit the APLT in apoptosing cells (determined by lipid movements investigated by flow cytometry). Little is known of the identities or mechanisms of elaboration, presentation or release of these PL signals for apoptotic cell recognition. Stepwise, it is hypothesized that ; i) oxidants and/or activation of PLA2s during apoptosis result in elaboration of signaling GPCho and GPSer species, ii) loss of APLT activity and activated PL flip-flop moves them across the plasma membrane in a manner that is, in part, driven by the PL species themselves, and iii) their release to the media, or retention on the surface of the apoptosing cell signals for phagocytic recruitment and non-phlogistic engulfment.