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Physiological cell death is a process the purpose of which is the elimination of functionally inappropriate cells in a manner that does not elicit an inflammatory response. We have shown previously that the ability of apoptotic corpses to be recognized by macrophages and to modulate the proinflammatory responses of those cells represents paradoxically a gain-of-function acquired during the physiological cell death process. Cells that die pathologically (that is, necrotic vs apoptotic corpses) also are recognized by macrophages but do not down-regulate macrophage inflammatory responses; the recognition of these two classes of native dying cells occurs via distinct and noncompeting mechanisms. We have examined the apoptotic modulation of proinflammatory cytokine gene transcription in macrophages (by real-time RT-PCR analysis) and the corresponding modulation of transcriptional activators (by transcriptional reporter analyses). Our data demonstrate that apoptotic cells target the proinflammatory transcriptional machinery of macrophages with which they interact, without apparent effect on proximal steps of Toll-like receptor signaling. The modulatory activity of the corpse is manifest as an immediate-early inhibition of proinflammatory cytokine gene transcription, and is exerted directly upon binding to the macrophage, independent of subsequent engulfment and soluble factor involvement. Recognition and inflammatory modulation represent key elements of an innate immune response that discriminates live from effete cells, and without regard to self.

The distinction between physiological (apoptotic) and pathological (necrotic) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are triggered by the cell corpses. Mechanistically, apoptotic cells die via an active and ordered pathway; necrotic deaths, conversely, are chaotic and passive. 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 deaths. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells to 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 cells, is not a specific ligand for the recognition of either one. The distinct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enhance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apoptotic cells profoundly inhibit phlogistic macrophage responses; this represents a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death. INTRODUCTIONCell death is vital to the morphological shaping of tissues in development and to the careful sculpting of functionally appropriate cellular repertoires (Surh and Sprent, 1994;Cecconi et al., 1998;Yeh et al., 1998;Yoshida et al., 1998). Selective cell deaths continue to play a role in the homeostasis of mature tissues. For example, the deletion of immune cells in the attenuation of an immune response (Webb et al., 1990;Kawabe and Ochi, 1991) and the elimination of cells that have become functionally inappropriate, including virally infected and transformed cells (Kägi et al., 1995), depend on the selective induction of cell death. The cell death process generally assures both that cells triggered to die will cease to function and that they will be cleared in an orderly manner.Cells that die in these physiological contexts typically are removed rapidly by phagocytic cells, including macrophages (Duvall et al., 1985;Savill et al., 1989). Of primary significance, these cell deaths ensue without inflammatory consequence (Kerr et al., 1972).Apoptosis is characterized by an orderly sequence of internal events, of which chromatin condensation is one, that precede the loss of cellular integrity (Russell, 1983;Wyllie et al., 1984;Harvey et al., 2000). Early studies also recognized that physiological cell deaths occur in a cell autonomous manner and that bystander cells are unaffected (Ucker et al., 1989;Dhein et al., 1995). Consistent with these observations, eng...