| Apoptosis |
| Active cellular death, largely controlled by a family of cysteine proteases called caspases
Apoptotic caspases are broadly grouped into initiator caspases (caspase-8 and -9) and executioner caspases (caspases-3, -6, and -7)
Intrinsic or mitochondrial pathway
Activated by stress-inducing stimuli (i.e., DNA damage, accumulation of unfolded proteins, and hypoxia) and developmental signals
Signals converge on the mitochondria, where pro-apoptotic and anti-apoptotic members of the BCL2 family mediate the release of cytochrome c, formation of the apoptosome with caspase-9 and APAF-1, which leads to the activation of the downstream executioner caspases, such as caspase-3 and caspase-7
Extrinsic pathway
Triggered by signals that engage extracellular death receptors (DR)
Tumor necrosis factor (TNF) and TNF receptor-1 (TNFR1)
CD95-ligand (CD95-L or Fas-L) and CD95 (or Fas)
TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL-R1/2 (DR4/5)
Recruitment of pro-caspase-8 to the death-inducing signaling complex (DISC) at the DR (with the adapter proteins FADD or TRADD), resulting in dimerization and activation of caspase-8, leading to caspase-3 and caspase-7 activity
Caspase-8 activity can also feed into the intrinsic pathway by cleaving and activating BCL2 family proteins |
Membrane ‘blebbing,' often with separation of apoptotic bodies
DNA fragmentation
Chromatin condensation
Considered immunologically silent due to the packaging of possible danger-associated molecular patterns (DAMPs) into discreet, tolerogenic pieces
Active phosphatidylserine (PtdSer) exposure (Annexin V positive)
Propidium iodide or 7-AAD negative at early stages |
1, 99, 100, 101, 102, 103
|
|
| Necrosis |
| Characterized as an passive type of cell death that occurs independently of caspase activation
Triggered in response to catastrophic damage or pathology, including infarction, mechanical trauma, ischemia, frostbite, and animal venom
Apoptotic cells that are not efficiently cleared by phagocytes can undergo secondary necrosis independently of any apoptotic machinery |
Cellular swelling (oncosis)
Organelle swelling
Nuclear distention
Cellular rupture
Releases inflammatory cellular contents (DAMPs) or alarmins that can activate neighboring immune cells via Toll-like receptor (TLR) signaling and other mechanisms
Annexin V positive due to membrane rupture
Propidium iodide or 7-AAD positive |
1, 104, 105, 106 |
|
| Necroptosis |
| Genetically programed cell death with the morphological features of necrosis
Triggered by diverse forms of neurodegeneration, ischemia, or infection.
Engagement of the extrinsic pathway (i.e., TNF–TNFR pathway) in the absence of caspase-8 can result in a necrotic cell death that requires the kinase activity of receptor interacting protein kinase1 (RIPK1) and RIPK3
RIPK3 phosphorylates and activates the pseudokinase, mixed lineage-kinase like (MLKL)
Induces a conformational change that allows for its oligomerization and interaction with the plasma membrane through binding to phosphatidylinositol lipids to directly disrupt membrane integrity
RIPK1 is required for a variety of innate immune signaling pathways, such as TLRs, interferons, and the RIG-I-MAVS pathway |
Loss of plasma membrane integrity
Swollen cellular organelles
Releases inflammatory cellular contents (DAMPs) or alarmins that can activate neighboring immune cells via TLR signaling and other mechanisms
Active PtdSer exposure (Annexin V positive)
Propidium iodide or 7-AAD positive |
5, 107, 108, 109, 110, 111, 112 |
|
| Pyroptosis |
| Non-apoptotic, genetically programmed cellular death mediated by excessive inflammatory caspase activity (human caspase-1, -4, and -5; rodent caspase-1 and -11)
Required for cell death in a variety of experimental settings, including in the immune system, the cardiovascular system, and the central nervous system
Caspase-1 is activated by dimerization at complexes termed inflammasomes that form in the cytosol and detect a diverse repertoire of pathogenic molecules, including bacterial toxins and viral RNA
Activated caspase-1 in turn cleaves pro-IL-1β and pro-IL-18, which facilitates the secretion of these pro-inflammatory cytokines
Characterized by caspase-1-dependent formation of plasma membrane pores, which leads to pathological ion fluxes that ultimately result in cellular lysis and release of inflammatory intracellular contents
Caspase-1 can also activate caspase-7 |
Cellular rupture
DNA fragmentation
Releases inflammatory cellular contents (DAMPs) or alarmins that can activate neighboring immune cells via TLR signaling and other mechanisms
Often Annexin V positive due to membrane rupture
Propidium iodide or 7-AAD positive |
1, 4, 6, 51, 113, 114 |
