Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells - Implications for the delayed clearance model of autoimmunity

Department of Medicine, Division of Nephrology, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Journal of Biological Chemistry (Impact Factor: 4.6). 03/2006; 281(8):4663-70. DOI: 10.1074/jbc.M508342200
Source: PubMed

ABSTRACT Current models of autoimmunity suggest that delayed clearance of apoptotic cells leads to the presentation of apoptotic antigens in the context of inflammatory signals, with resultant autoimmunity. These models implicitly assume that, in contrast to early apoptotic cells (that retain membrane integrity), late apoptotic cells (with compromised membranes) act like necrotic cells (which also lack intact membranes), possibly because of the release of proinflammatory intracellular contents. We showed previously that early apoptotic and necrotic cells induce distinct mitogen-activated protein kinase modules in macrophages with which they interact. Exposure to apoptotic cells led to nearly complete inhibition of both basal and macrophage colony-stimulating factor-induced ERK1/2 by macrophages. In contrast, necrotic cells induced ERK1/2. We show here that apoptotic cells also strongly induced both c-Jun N-terminal kinase and p38, whereas necrotic cells had no detectable effect on c-Jun N-terminal kinase and p38. We also compared the signaling events induced in macrophages by exposure to early apoptotic cells, late apoptotic cells, and necrotic cells. The signaling events induced by late apoptotic cells were identical to and just as potent as those induced by early apoptotic cells. Thus, apoptotic cells are functionally equivalent throughout the cell death process, irrespective of membrane integrity. Moreover, the effects of both early and late apoptotic cells on signaling were dominant over those of necrotic cells. These data show that apoptotic cells do not become proinflammatory upon the loss of membrane integrity and are inconsistent with the notion that delayed clearance alone can lead to autoimmunity.

  • Source
    • "Cells that die pathologically (that is, a " necrotic " vs. an " apoptotic " death) also are recognized by responder cells but do not modulate inflammatory responses (Cocco and Ucker, 2001; Cvetanovic and Ucker, 2004; Cvetanovic et al., 2006). The recognition of these two classes of dying cells proceeds to comparable extents, albeit via distinct and non-competing processes (Cocco and Ucker, 2001; Patel et al., 2006). Our earlier experiments with cytochalasin D (Figure 4E) indicated that PWV interaction reflects a proximal recognition event and is dissociable from immunomodulatory consequences of recognition. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptotic recognition is innate and linked to a profound immune regulation ("Innate Apoptotic Immunity", IAI), involving anti-inflammatory and immunosuppressive responses. Many of the molecular and mechanistic details of this response remain elusive. While immune outcomes can be quantified readily, the initial specific recognition events have been difficult to assess. We have developed a sensitive, real-time method to detect the recognition of apoptotic cells by viable adherent responder cells, employing a photonic crystal biosensor approach. The method relies upon characteristic spectral shifts resulting from the specific recognition and dose-dependent interaction of adherent responder cells with non-adherent apoptotic targets. Notably, the biosensor provides a readout of early recognition-specific events in responder cells that occur distal to the biosensor surface. We find that innate apoptotic cell recognition occurs in a strikingly species-independent manner, consistent with our previous work and inferences drawn from indirect assays. Our studies indicate obligate cytoskeletal involvement, although apoptotic cell phagocytosis is not involved. Because it is a direct, objective, and quantitative readout of recognition exclusively, this biosensor approach affords a methodology with which to dissect the early recognition events associated with IAI and immunosuppression.
    Molecular biology of the cell 04/2014; 25(11). DOI:10.1091/mbc.E13-11-0700 · 5.98 Impact Factor
  • Source
    • "Yet, the range of action and the phagocyte sensors remain to be resolved. Note that plasma membrane-damaged cells (i.e. late apoptotic and necrotic cells) can also release or expose endogenous and exogenous signals, known as alarmins or damageassociated molecular patterns (DAMPs), to alert the organism to tissue injury (Patel et al., 2006; Peter et al., 2010) (Table 1). One such protein is the high mobility group box 1 protein (HMGB-1), which is released from necrotic cells, but not during apoptosis, and actively stimulates the secretion of proinflammatory cytokines (Scaffidi et al., 2002; Andersson et al., 2000). "
    Atherogenesis, 01/2012; , ISBN: 978-953-307-992-9
  • Source
    • "However, both apoptotic and necrotic cells are suggested to use the same signaling apparatus for cell recognition (Chung et al., 2000). Further work is clearly needed to define the molecular events that dictate the type of phagocytic cup formed in response to recognition, because this could have important implications for subsequent processing of the engulfed target in the phagocyte (Patel et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Programmed cell death is critical both for organ formation during development and during adult life, when billions of cells must be removed every day. The culmination of the apoptotic process is the specific recognition and engulfment of the apoptotic cell by a phagocyte. A number of recent studies have revealed a series of evolutionarily conserved proteins that link corpse recognition to membrane movement, facilitating the internalization of the target and its subsequent degradation. Two potential signaling modules have been identified: one involving the CED-12/ELMO and CED-5/Dock180 proteins, which function as a bipartite guanine nucleotide exchange factor (GEF) for Rac1, and a second involving CED-1/LRP1 (a potential engulfment receptor) and the adaptor protein CED-6/GULP. Recognition of the apoptotic cell modulates cytokine secretion by the phagocyte, resulting in an anti-inflammatory state distinct from that induced by necrotic cells. The recent molecular delineation of the phagocytic process and the identification of novel signaling proteins involved in engulfment have provided an exciting new platform for future studies into this biologically important process.
    Journal of Cell Science 08/2007; 120(Pt 13):2143-9. DOI:10.1242/jcs.03463 · 5.33 Impact Factor
Show more


Available from