Classification: Accidental or Programmed
When pathogenic factors act, two main outcomes are possible: necrosis followed by lysis (necrolysis) or apoptosis followed by phagocytosis. Globally, all types of cell death are divided into two large groups.
First is accidental necrosis. It represents an unregulated process occurring in response to severe external trauma. The cell swells, and its membrane ruptures. This releases DAMPs (Damage-Associated Molecular Patterns), which serve as danger signals.
The second group is regulated forms of death. These are genetically programmed processes, which include apoptosis, necroptosis, ferroptosis, and pyroptosis.
Apoptosis: "Quiet" Death
Apoptosis is a classic example of programmed death that does not cause inflammation.
- Key enzymes: The process is executed with the participation of caspase-8 and caspase-3.
- Morphology: The cell does not rupture; instead, it neatly breaks down into fragments called apoptotic bodies, which are subsequently phagocytosed by other cells.
- Secretion: Anti-inflammatory molecules are released, and the cell's contents do not spill into the extracellular environment.
Regulated Death with Inflammation
Unlike apoptosis, other forms of programmed death are accompanied by the release of DAMPs and an inflammatory response.
- Necroptosis. Triggered in the absence or inactivation of caspase-8. Externally resembles accidental necrosis (membrane rupture occurs), but is strictly genetically controlled. Accompanied by the release of cytokines (e.g., IL-6) and chemokines.
- Ferroptosis. The mechanism relies on lipid peroxidation of cell membranes. The process depends on iron and glutathione. A key factor is the impaired function of the enzyme glutathione peroxidase 4 (GPX4), leading to the accumulation of reactive oxygen species (ROS).
- Pyroptosis. Death accompanied by pronounced inflammation. It involves specific human enzymes: h-caspase-1, h-caspase-4, and h-caspase-5. The cell secretes pro-inflammatory cytokines, specifically IL-1$\beta$ and IL-18.
Cellular Debris Clearance: Lysis and Autophagy
Following the death of a cell or its organelles, their destruction takes place. Lysis (destruction of the dead cell) proceeds via two pathways:
- Autolysis (self-destruction) is mediated by lysosomal enzymes activated within the cell itself. Excess ROS and free radicals participate in this process.
- Heterolysis destruction occurs with the participation of other cells (phagocytes) or microorganisms.
A distinct variant of lysis is immunogenic cell death. Its goal is the elimination of foreign (e.g., viral) or endogenous antigens by activating adaptive immune response mechanisms.
For the destruction of damaged or obsolete intracellular organelles, autophagy exists:
- Microautophagy: Lysosomes fuse with denatured macromolecules or membrane fragments for hydrolysis.
- Macroautophagy: A large vacuole is formed—the autophagosome (derived from fragments of the plasmalemma, cytoplasm, and altered organelles). It fuses with a lysosome to form an autolysosome, where hydrolysis occurs.
- Chaperone-mediated autophagy: Transport of denatured proteins into the lysosome. Chaperones of the hsc70 pool bind to the protein, and the lysosome-associated membrane protein LAMP-2 acts as a receptor for this complex.