Inflammasome

Inflammasomes are cytosolic multiprotein complexes of the innate immune system responsible for the activation of inflammatory responses and cell death. They are formed as a result of specific cytosolic pattern recognition receptors (PRRs), which are molecular sensors of microbe-derived pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) from the host cell, or homeostatic disruptions. Activation and assembly of the inflammasome promotes the activation of caspase-1, which then proteolytically cleaves pro-inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as the pore-forming molecule gasdermin D (GSDMD). The N-terminal GSDMD fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, which is responsible for the release of mature cytokines. Additionally, inflammasomes can act as integral components of larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis. Inflammasome formation is driven by germline-encoded PRRs, including NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors), AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16), and pyrin. Through their caspase activation and recruitment domain (CARD) or pyrin domain (PYD), the PRRs interact with the adaptor protein called apoptosis-associated speck like protein containing a CARD (also known as ASC or Pycard), which then recruits pro-caspase-1 via its CARD domain to activate inflammatory signaling and pyroptotic cell death. Notably, the PYD of the adaptor protein ASC has been demonstrated to function as a prion-like domain, forming a self-perpetuating polymer when activated. In addition to inflammasomes activating caspase-1, several studies also described non-canonical inflammasome complexes that act independently from caspase-1. In mice, the non-canonical inflammasome is activated by direct sensing of cytosolic bacterial lipopolysaccharide (LPS) by caspase-11, which subsequently induces pyroptotic cell death. In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5....