Programmed cell death characterized by orderly cellular dismantling without inflammatory consequences. Apoptosis removes damaged, infected, or unnecessary cells while maintaining tissue homeostasis and preventing autoimmunity through proper clearance (efferocytosis).
Two main pathways: (1) Intrinsic (mitochondrial): cellular stress, DNA damage, or growth factor withdrawal causes BAX/BAK activation, mitochondrial outer membrane permeabilization, cytochrome c release, apoptosome formation, and caspase-9 activation. (2) Extrinsic (death receptor): FAS, TRAIL, or TNF-R engagement activates caspase-8. Both converge on executioner caspases (3, 6, 7) causing DNA fragmentation, membrane blebbing, and exposure of 'eat-me' signals (phosphatidylserine). Apoptotic cells are cleared by macrophages (efferocytosis) without inflammation.
Defective apoptosis underlies autoimmune disease (failure to delete autoreactive lymphocytes), cancer (resistance to cell death), and neurodegeneration (excessive neuronal apoptosis). In cPNI, proper apoptosis-efferocytosis is essential for resolution of inflammation. Impaired efferocytosis causes secondary necrosis and chronic inflammation. Assessing apoptosis resistance in cancer or autoimmunity guides treatment; supporting apoptosis clearance reduces autoinflammation.
- Characterized by cell shrinkage, membrane blebbing, nuclear fragmentation
- Exposes phosphatidylserine as 'eat-me' signal for macrophages
- Does NOT trigger inflammation (unlike necrosis)
- Intrinsic pathway: mitochondrial, triggered by cellular stress
- Extrinsic pathway: death receptors (FAS, TNF-R, TRAIL)
- Caspases are executioner proteases cleaving ~600 cellular substrates
- P53 'guardian of genome' triggers apoptosis in DNA damage
- BCL-2 family regulates mitochondrial pathway (pro- and anti-apoptotic members)
- Efferocytosis (clearance) prevents secondary necrosis and autoimmunity
- Cancer cells evade apoptosis via BCL-2 overexpression, p53 mutation
- efferocytosis — Apoptotic cell clearance by macrophages preventing inflammation
- macrophages — Phagocytose apoptotic cells via phosphatidylserine recognition
- phosphatidylserine — Exposed on apoptotic cells as 'eat-me' signal
- inflammation — Apoptosis does not cause; impaired clearance does
- necrosis — Inflammatory cell death contrasting with silent apoptosis
- p53 — Tumor suppressor triggering apoptosis in DNA damage
- caspases — Protease family executing apoptosis
- mitochondria — Central to intrinsic apoptosis pathway via cytochrome c release
- cytochrome c — Released from mitochondria to form apoptosome
- BCL-2 — Anti-apoptotic protein; overexpressed in cancer
- cancer — Resistance to apoptosis hallmark of cancer
- autoimmune disease — Defective apoptosis of autoreactive lymphocytes
- neurodegeneration — Excessive neuronal apoptosis in Alzheimer's, Parkinson's
- DNA damage — Triggers p53-mediated apoptosis
- oxidative stress — Induces mitochondrial apoptosis pathway
- TNF — Can trigger extrinsic apoptosis via TNF receptors
- FAS — Death receptor mediating T cell apoptosis
- T cells — Undergo apoptosis for clonal selection and homeostasis
- resolution of inflammation — Apoptosis of immune cells necessary for resolution