inflammasomale

An inflammasome is a multiprotein complex that senses microbial components and cellular stress to initiate inflammatory responses. It typically consists of a sensor protein from the NOD-like receptor (NLR) or PYHIN families, the adaptor protein ASC, and the effector enzyme caspase-1. Once assembled, caspase-1 cleaves the proforms of the cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their active forms and also cleaves gasdermin D, whose N-terminal fragment forms membrane pores that drive pyroptotic cell death and amplify inflammation.

Common inflammasome sensors include NLRP3, NLRC4, AIM2, and pyrin. Activation typically follows a two-signal model: priming, which upregulates pro-IL-1β and pro-IL-18 via NF-κB signaling; and activation, triggered by diverse stimuli such as potassium efflux, crystalline or microbial components, or toxins, leading to assembly of the inflammasome complex. There are canonical inflammasomes (caspase-1 dependent) and non-canonical pathways involving caspases-4 and -5 in humans or caspase-11 in mice, which respond to intracellular lipopolysaccharide and can also promote gasdermin D–mediated pore formation.

Biological significance includes host defense against pathogens and regulation of sterile inflammation. Dysregulation of inflammasome activity is linked to autoinflammatory and metabolic diseases, including cryopyrin-associated periodic syndrome (CAPS), gout, atherosclerosis, and neurodegenerative conditions.

Therapeutic approaches target IL-1 signaling, caspase-1, or specific inflammasome sensors. Examples include IL-1 blockers (anakinra, canakinumab), colchicine in gout, and investigational inhibitors such as MCC950 for NLRP3.