Efferocytosis: The mechanism for apoptotic cell clearance

Phagocytosis of apoptotic cells is a critical component of normal tissue homeostasis and the resolution of inflammation. The study of apoptotic cell clearance has been ongoing for nearly twenty years. However, it is currently unclear what changes on the surface of the apoptotic cell signals for their specific recognition and removal, and how each of the receptors proposed to be involved in phagocytosis of apoptotic cells participate in the engulfment process. Therefore, the goal of this work was to identify surface changes on the apoptotic cell required for engulfment, and to characterize the mechanism by which apoptotic cells are phagocytosed. As cells undergo apoptosis, they lose the ability to maintain normal phospholipid asymmetry and as a result, phosphatidylserine (PS) becomes exposed on the outer leaflet of the plasma membrane. Here, I show that the presence of PS is required for efficient engulfment to occur, regardless of the type of phagocyte involved in its removal, and that a newly identified receptor, the PSR, may be involved in PS recognition. Further, I demonstrate that the mechanism of apoptotic cell engulfment more closely resembles the process of macropinocytosis than the classical zipper-like mechanism utilized during phagocytosis of IgG-opsonized particles. However, phagocytosis of apoptoic cells, in comparison to macropinocytosis, is acutely sensitive to cholesterol levels within the plasma membrane and the organization of lipid raft domains. As the term macropinocytosis implies uptake of fluid, macromolecules, and microorganisms from the extracellular space, and is not generally considered to be capable of driving uptake of whole cells or cell bodies, the term “efferocytosis”, derived from the Latin prefix “effero-” meaning “to carry to the grave, to bury” is proposed to describe this unique phagocytic mechanism and to distinguish it from other described mechanisms of phagocytosis. This work is among the first to describe the mechanism for apoptotic cell engulfment, efferocytosis, and to identify both a ligand on the apoptotic cell, PS, and a receptor on the phagocyte, the PSR, which may autonomously initiate alterations in the cytoskeleton which result in the removal of the cell body.*; *Please refer to dissertation for diagram.