inflammasome

Inflammasomes are multiprotein complexes that detect microbial components and danger signals inside cells and initiate inflammatory responses. They promote the activation of inflammatory caspases, most notably caspase-1, which in turn processes pro-inflammatory cytokines such as pro-IL-1β and pro-IL-18 into their mature, secreted forms. Activation of caspase-1 also drives pyroptosis, a lytic form of programmed cell death, through gasdermin D pore formation that allows release of cytokines and cellular contents.

Canonical inflammasomes kit out from a sensor protein, an adaptor, and an effector. Sensor molecules include NLRP3, NLRC4, AIM2, and pyrin. The adaptor, ASC (PYCARD), links the sensor to caspase-1. Upon priming by priming signals such as microbial products or cytokines, cells upregulate components of the inflammasome and pro-IL-1β/pro-IL-18. Activation signals lead to assembly of an ASC speck, recruitment and activation of caspase-1, cytokine maturation, and gasdermin D–mediated pyroptosis.

Noncanonical inflammasomes involve caspase-4 and caspase-5 in humans (caspase-11 in mice) and are activated by cytosolic lipopolysaccharide. This pathway can directly induce gasdermin D–dependent pyroptosis and can subsequently stimulate canonical inflammasome responses.

Physiological roles include host defense against infection and participation in sterile inflammatory processes. Dysregulation is linked to autoinflammatory and metabolic diseases such as CAPS, gout, atherosclerosis, and neurodegenerative disorders. Therapeutic approaches target IL-1 signaling (e.g., anakinra, canakinumab), NLRP3 inhibitors, or caspase-1 inhibitors to modulate inflammasome-driven inflammation. Regulation occurs through transcriptional control, post-translational modifications, autophagy, and mitochondrial signals that influence activation thresholds.