Apoptosis is a form of programmed cell death that is essential in such processes as organ and tissue remodeling and the development and maturation of hematopoietic cells. The clearance of apoptotic cells is essential to prevent autoimmune responses to sequestered antigens that are exposed during the process of apoptosis and is largely mediated by phagocytes of the macrophage/monocyte lineage. Before phagocytosis can occur, macrophages must first be recruited to the apoptotic cells through chemotaxis. Products of the reaction catalyzed by the phospholipases A2 (PLA2) have been shown to induce monocyte chemotaxis. Some investigators have implicated a cytosolic calcium-independent PLA2 in the production of these products during apoptosis. However, a recent report suggests that secreted group Ila sPLA2 binds to the surfaces of apoptotic cells. The """"""""receptor"""""""" for this pool of sPLA2 is the rod domain of vimentin, an intermediate filament protein that is exposed when cells undergo apoptosis. Disintegration of the intermediate filament network by specific caspases precedes nuclear disintegration and is one of the initial events that occurs in apoptotic cells. Based on these observations, we hypothesize that the exposure of vimentin on apoptotic cells traps a pool of catalytically active sPLA2 that then generates the bioactive lipids and induce macrophage chemotaxis. To test this hypothesis, we will further characterize the interactions between vimentin and the sPLA2s, in particular the group V enzyme that readily hydrolyzes the zwitterionic phospholipids in the outer leaflet of the plasma membrane. We will also perform experiments to determine if the vimentin-associated pool of sPLA2 enhances the recruitment of macrophages to apoptotic cells. All together, these studies should provide insights into a novel function of sPLA2 and may suggest new ways to enhance the clearance of apoptotic cells and thereby prevent autoimmune responses.
