page_title: Pyroptosis
section_title: The canonical inflammasome pathway
hierarchical_section_title: Pyroptosis / Mechanism / The canonical inflammasome pathway
caption_attribution_description: English: Inflammasome, a multiprotein complex that mediates the activation of Caspase-1. Dysregulation of inflammasomes has also been linked to a number of autoinflammatory and autoimmune disorders.
context_page_description: Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. 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. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.
  The process is initiated by formation of a large supramolecular complex termed the inflammasome upon intracellular danger signals. Inflammasome activates a different set of caspases as compared to apoptosis, for example, caspase-1/4/5 in humans and caspase-11 in mice. These caspases contribute to the maturation and activation of several proinflammatory cytokines and pore-forming protein gasdermins. Formation of pores causes cell membrane rupture and release of cytokines, as well as various damage-associated molecular pattern molecules such as HMGB-1, ATP and DNA, out of the cell. These molecules recruit more immune cells and further perpetuate the inflammatory cascade in the tissue.
context_section_description: In the canonical inflammasome pathway, PAMPs and DAMPs are recognised by certain endogenous PRRs. For example, NLR proteins NLRC4 can recognise flagellin and type III secretion system components. NLRP3 is  activated by cellular events induced by different PAMPs and DAMPs stimuli. Some non-NLR proteins like absent in melanoma 2 (AIM2) and pyrin can also be activated and form inflammasomes. Also, non-inflammasome-forming PRRs such as TLRs, NOD1 and NOD2 also play important roles in 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. In addition, pro-IL-1β and pro-IL-18 is released to be processed by cysteine-mediated caspase-1.
  Canonical inflammasomes mostly contain three components: a sensor protein (PRRs), an adaptor (ASC) and an effector (caspase-1). Generally, inflammasome-forming NLR proteins share a similar structure, several leucine-rich repeat (LRR) domains, a central nucleotide-binding and oligomerization domain (NBD) and an N-terminal pyrin domain (PYD). NLRP3, for example, recruits ASC adaptor protein via PYD-PYD interaction. Both pro-caspase-1 and ASC contain a caspase activation and recruitment domain (CARD), and this homotypic CARD-CARD interaction enables autocatalytic cleavage and reassembly of procaspase-1 to form active caspase-1. Alternatively, NLRC4 can directly recruit pro-caspase-1, as it has a CARD domain instead of a pyrin domain.
  Activated caspase-1 is responsible for cleavage of  pro-IL-1β and pro-IL-18. These cytokines, once processed, will be in their biologically active form ready to be released from the host cells. In addition, caspase-1 also cleaves the cytosolic gasdermin D (GSDMD). GSDMD can be cleaved to produce an N-terminal domain (GSDMD-N) and a C-terminal domain (GSDMD-C). GSDMD-N can oligomerize and form transmembrane pores that have an inner diameter of 10-14nm. The pores allow secretion of IL-1β and IL-18 and various cytosolic content to extracellular space, and they also disrupt the cellular ionic gradient. 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.Also, GSDMD-N can only insert itself into the inner membrane with specific lipid compositions, which limits its damage to neighbour cells.
caption: The formation of NLRP3 inflammasome
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