NLR family pyrin domain-containing 1 and 3 inflammasome (NLRP1/NLRP3 inflammasome)

The NLR family pyrin domain-containing 1 (NLRP1) and 3 (NLRP3) inflammasomes are cytosolic multiprotein complexes that play a fundamental role in the innate immune system by sensing a diverse array of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) [1.1.3, 1.2.1]. Upon activation, these sensor proteins oligomerize and recruit the adaptor protein ASC and the effector protease pro-caspase-1, forming a platform that facilitates the maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), as well as the induction of pyroptosis [1.1.4, 1.2.4]. NLRP3 is the most extensively characterized inflammasome and is triggered by various stimuli such as ionic flux, mitochondrial dysfunction, and environmental irritants, while NLRP1 is uniquely activated through 'functional degradation' initiated by pathogen-encoded proteases or metabolic stress [1.1.1, 1.2.3]. Dysregulation of these pathways is linked to numerous inflammatory, metabolic, and neurodegenerative conditions, including cryopyrin-associated periodic syndromes (CAPS), Alzheimer's disease, atherosclerosis, and type 2 diabetes [1.2.2, 1.3.3]. Consequently, the NLRP1 and NLRP3 inflammasomes are high-priority therapeutic targets, with several small-molecule inhibitors like dapansutrile and MCC950 in development to selectively modulate these inflammatory responses [1.3.2, 1.4.2]. Targeting these complexes offers the potential to treat chronic inflammatory diseases at their source, although challenges remain regarding the maintenance of host defense against infections [1.4.3, 1.5.1].

Other names

NLRP1 inflammasomeNLRP3 inflammasomeNALP1NALP3CryopyrinCIAS1PYPAF1CARD7DEFCAPNAC

Inhibitors of the NLRP3 inflammasome typically bind to the NACHT domain, inhibiting its ATPase activity and preventing the conformational change required for oligomerization and ASC recruitment [1.2.3, 1.2.4]. For NLRP1, therapeutic strategies involve preventing its 'functional degradation' or blocking the release of the active C-terminal fragment [1.1.1, 1.1.4]. Dual inhibitors like ADS032 target both sensors to provide a broader anti-inflammatory effect [1.3.2].