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Review
. 2005 Apr;73(4):1907-16.
doi: 10.1128/IAI.73.4.1907-1916.2005.

Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells

Susan L Fink  1 , Brad T Cookson
Affiliations
Review

Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells

Susan L Fink et al. Infect Immun. 2005 Apr.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Caspases are classified into functional subgroups. Caspases are cysteine proteases that are expressed as inactive precursor enzymes with an N-terminal prodomain followed by a two-subunit effector domain. Members of the caspase family can be classified based on their physiologic roles and substrate specificities. They are divided into two main groups: those involved in apoptosis (caspase-2, -3, -6, -7, -8, -9, and -10) and those related to caspase-1 (caspase-1, -4, -5, -13, and -14, as well as murine caspase-11 and -12), whose primary role appears to be cytokine processing and proinflammatory cell death. The caspases implicated in apoptosis can be further divided into initiator and effector subgroups. Initiator caspases (caspase-2, -8, -9, and -10) have long prodomains and function to activate effector caspases (caspase-3, -6, and -7), which have small prodomains and cleave a variety of cellular substrates. CARD, caspase recruitment domain; DED, death effector domain.
FIG. 2.
FIG. 2.
Pathways leading to cell death. Healthy cells respond to death-inducing stimuli by initiating a variety of molecular pathways leading to cell death. Completion of the proper pathway is a critical cellular function to ensure that the appropriate outcome is ultimately achieved in a multicellular organism. Failure to die in response to particular stimuli can result in abortive embryogenesis and organ dysfunction and contributes to the initiation of cancer. Proinflammatory death is vital in triggering appropriate immune responses or, in the extreme, may cause tissue pathology and organ dysfunction. Therefore, pathway utilization can dramatically influence biological systems. Apoptosis is a pathway leading to cell death that features the activation of initiator caspases that activate effector caspases to cleave cellular substrates. Apoptotic cells demonstrate cytoplasmic and nuclear condensation, DNA damage, formation of apoptotic bodies, maintenance of an intact plasma membrane, and exposure of surface molecules targeting intact cell corpses for phagocytosis. In the absence of phagocytosis, apoptotic bodies may proceed to lysis and secondary or apoptotic necrosis. Autophagy features degradation of cellular components within the intact dying cell in autophagic vacuoles. The morphological characteristics of autophagy include vacuolization, degradation of cytoplasmic contents, and slight chromatin condensation. Autophagic cells can also be taken up by phagocytosis. Oncosis is the prelethal pathway leading to cell death accompanied by cellular and organelle swelling and membrane breakdown, with the eventual release of inflammatory cellular contents. Pyroptosis is a pathway to cell death mediated by the activation of caspase-1, a protease that also activates the inflammatory cytokines, IL-1β, and IL-18. This pathway is therefore inherently proinflammatory. Pyroptosis also features cell lysis and release of inflammatory cellular contents. Undoubtedly, other pathways exist that have not yet been described.
FIG. 3.
FIG. 3.
Biological input differentially influences utilization of cell death pathways. Factors influencing cell death include the stimulus, cell type, and the surrounding milieu of the cell and, therefore, its physiological state during receipt of the stimulus, which together dictate the pathway of cell death. In column A1, a stimulus (1) delivered to a cell type of interest in its baseline physiological state (α) dictates cell death via the primary pathway (P). Altering the magnitude of the stimulus (Δ1), e.g., multiplicity of infection, concentration, or concentration per unit time, can alter the path to cell death (A2, leading to pathway Q), as does the physiological state (β) of the cell during stimulation (A3, leading to pathway R) and the cell type being studied (A4, leading to pathway S). A single stimulus can simultaneously trigger multiple pathways (column B), and blockade of the primary pathway for a given cell type (column C versus column A1) can result in the use of alternate pathway(s) (column C). Finally, multiple stimuli (2,3, or 4), which may utilize a variety of upstream signaling cascades, may converge in the use of biologically conserved effector pathways and result in cell death (column D).
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