Programmed cell clearance: molecular regulation of the elimination of apoptotic cell corpses and its role in the resolution of inflammation

Abstract

Programmed cell clearance is a physiological process of elimination of apoptotic cell corpses. Recent studies have disclosed several ligand-receptor interactions that dictate the recognition or non-recognition of cells by macrophages and other phagocytes. The externalization of the anionic phospholipid, phosphatidylserine is effectively recognized by specific receptors on professional phagocytes and facilitates the clearance of apoptotic cells. Macrophage disposal of cells at sites of inflammation is believed to play an important role in the resolution of the inflammatory process, and recent studies have suggested a role for the NADPH oxidase in the process of macrophage elimination of activated neutrophils. The present review will focus on the molecular regulation of programmed cell clearance, and discuss the role of cell elimination in the resolution of inflammation.

Fig 1

Hypothetical diagram illustrating the dual role of the NADPH oxidase in programmed cell clearance. Macrophage recognition and clearance of activated neutrophils at sites of inflammation is believed to play a critical role in the resolution of inflammation. Our studies have shown that the NADPH oxidase is required for PS oxidation and externalization in activated human neutrophils [33]. The absence of PS exposure in neutrophils that lack expression of a functional oxidase results in inefficient clearance of these cells by professional phagocytes. In addition, the NADPH oxidase was shown to play a role in the engulfing cell during programmed cell clearance [34]. The molecular pathways governed by the NADPH oxidase in macrophages remain to be understood, but one may speculate that the NADPH oxidase is required to produce reactive oxygen species (ROS) in the target cell whereas in the engulfing cell, the regulation of intracellular pH is important. Further studies are warranted to test this hypothesis.