Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure

The distinction between physiological (apoptotic) and pathological (necroti c) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are tri ggered by the cell corpses. Mechanistically, apoptotic cells die via an act ive and ordered pathway; necrotic deaths, conversely, are chaotic and passi ve. Macrophages and other phagocytic cells recognize and engulf these dead cells. This clearance is believed to reveal an innate immunity, associated with inflammation in cases of pathological but not physiological cell death s. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells t o similar extents and with similar kinetics. However, recognition of these two classes of dying cells occurs via distinct and noncompeting mechanisms. Phosphatidylserine, which is externalized on both apoptotic and necrotic c ells, is not a specific ligand for the recognition of either one. The disti nct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enh ance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apopto tic cells profoundly inhibit phlogistic macrophage responses; this represen ts a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death .