Pyroptosis
This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses.
[1] The process is initiated by formation of a large supramolecular complex termed the inflammasome (also known as a pyroptosome) upon intracellular danger signals.
[3] These caspases contribute to the maturation and activation of the pro-inflammatory cytokines IL-1β and IL-18, as well as the pore-forming protein gasdermin D. Formation of pores causes cell membrane rupture and release of cytokines, as well as various damage-associated molecular pattern (DAMP) molecules such as HMGB-1, ATP and DNA, out of the cell.
[6][7][8] This type of inherently pro-inflammatory programmed cell death was named pyroptosis in 2001 by Molly Brennan and Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine at the University of Washington.
The compound term of pyroptosis may be understood as "fiery falling", which describes the bursting of pro-inflammatory chemical signals from the dying cell.
[16] In a cell that undergoes pyroptosis, gasdermin pores are formed on the plasma membrane, resulting in water influx.
Cells that undergo pyroptosis exhibit membrane blebbing and produce protrusions known as pyroptotic bodies, a process not found in necroptosis.
[20] Recognition of PAMPs and DAMPs triggers the formation of multi-protein complex inflammasomes, which then activates caspases to initiate pyroptosis.
These receptors upregulate expression of inflammatory cytokines such as IFN α/β, tumour necrosis factor (TNF), IL-6 and IL-12 through NF-κB and MAPK-signaling pathways.
The resulting increase in osmotic pressure causes an influx of water followed by cell swelling and bursting.
Notably, GSDMD-N is autoinhibited by GSDMD C-terminal domain before cleavage to prevent cell lysis in normal conditions.
[29] Also, GSDMD-N can only insert itself into the inner membrane with specific lipid compositions,[30] which limits its damage to neighbour cells.
[15] The noncanonical inflammasome pathway is initiated by binding of lipopolysaccharide (LPS) of gram-negative bacteria directly onto caspase-4/5 in humans and caspase-11 in murines.
[6] When the "danger" signal is sensed, the quiescent cells will be activated to undergo pyroptosis and produce inflammatory cytokines IL-1β and IL-18.
)[32] The cell activation results in an increase in cytokine levels, which will augment the consequences of inflammation and this, in turn, contributes to the development of the adaptive response as infection progresses.
If the amplification cycles persist, metabolic disorder, autoinflammatory diseases and liver injury associated with chronic inflammation will occur.
Principally, pyroptosis can kill cancer cells and inhibit tumour development in the presence of endogenous DAMPs.
Also, cellular concentration of GSDME increases when gastric cancer cells are treated with certain chemotherapy drugs.
AIM2 protein can recognise viral DNA in cytoplasm and form AIM2 inflammasome, which then triggers by a caspase-1 dependent canonical pyroptosis pathway.
Although pyroptosis contributes to the host's ability to rapidly limit and clear infection by removing intracellular replication niches and enhancing defensive responses through the release of proinflammatory cytokines and endogenous danger signals, in pathogenic inflammation, such as that elicited by HIV-1, this beneficial response does not eradicate the primary stimulus.
Of note, Caspase-1 deficient mice develop normally,[44][45] arguing that inhibition of this protein would produce beneficial rather than harmful therapeutic effects in HIV patients.
