NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome (NLRP3 inflammasome)

The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a multi-protein cytosolic complex that serves as a key component of the innate immune system (UniProt: P59496). It is primarily expressed in myeloid cells, including dendritic cells, where it acts as a sensor for a diverse array of pathogen-associated molecular patterns (PAMPs) and sterile danger signals (DAMPs) (PubMed: 31034466). Upon activation, the NLRP3 protein oligomerizes and recruits the adapter protein ASC and the effector protease pro-caspase-1, forming a functional inflammasome complex. This assembly leads to the catalytic activation of caspase-1, which subsequently processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their bioactive forms and may induce a form of programmed cell death known as pyroptosis (PubMed: 27951881). In dendritic cells, the release of these cytokines is pivotal for the activation and polarization of T-cells, thereby bridging innate and adaptive immunity (PubMed: 28553955). Dysregulation of the NLRP3 inflammasome is strongly linked to the pathogenesis of various inflammatory and autoimmune diseases, such as cryopyrin-associated periodic syndromes (CAPS), gout, type 2 diabetes, and Alzheimer's disease (PubMed: 30007736). Consequently, NLRP3 has emerged as a high-priority therapeutic target. Several small-molecule inhibitors, including dapansutrile (OLT1177) and tranilast, are being investigated in clinical trials for their ability to specifically block NLRP3 activation and reduce pathological inflammation (PubMed: 30104476). These drugs typically function by inhibiting the ATPase activity of the NLRP3 NACHT domain or by preventing the conformational changes required for inflammasome assembly. Monitoring efficacy in clinical settings often involves measuring systemic levels of IL-1β and IL-18 as biomarkers of inflammasome activity (PubMed: 29385444).

Other names

CryopyrinCaspase recruitment domain-containing protein 7CIAS1NALP3PYPAF1

Direct inhibition of the NLRP3 protein's ATPase activity or prevention of the assembly of the inflammasome complex, thereby blocking the activation of caspase-1 and the subsequent release of pro-inflammatory cytokines IL-1β and IL-18.