NLRP3

NLRP3, or NLR family pyrin domain-containing 3, is a cytosolic pattern recognition receptor that forms the NLRP3 inflammasome, a central component of the innate immune system’s response to cellular stress and infection. It detects a broad range of PAMPs and DAMPs and mediates inflammation through caspase-1 activation and cytokine maturation.

Structure: NLRP3 is a ~1036 amino acid protein in humans with an N-terminal pyrin domain (PYD), a central NACHT domain responsible for nucleotide binding and oligomerization, and C-terminal leucine-rich repeats. The PYD enables homotypic interaction with the adaptor protein ASC, which contains PYD and CARD domains and recruits pro-caspase-1 via CARD.

Activation mechanism: Activation requires priming, often through NF-κB–mediated transcription of NLRP3 and pro-IL-1β, followed by an activation signal such as potassium efflux, extracellular ATP, nigericin, or phagolysosomal damage from crystalline or particulate matter (uric acid, cholesterol, silica, amyloid-β). NLRP3 oligomerizes and recruits ASC; ASC then activates pro-caspase-1 via CARD interaction. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 and cleaves gasdermin D, producing pores and promoting pyroptotic cell death and cytokine release.

Regulation: NLRP3 activity is controlled by transcriptional priming, post-translational modifications (ubiquitination, phosphorylation), and autophagic degradation; several proteins and microRNAs modulate assembly and signaling.

Clinical significance: Gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome, Muckle-Well syndrome, and CINCA. Treatments include IL-1 blockers (anakinra, canakinumab) and NLRP3 inhibitors (experimental MCC950). Beyond monogenic disease, NLRP3 participates in gout, atherosclerosis, type 2 diabetes, Alzheimer's disease, and other sterile inflammatory conditions, making it a target for therapeutic development.