NLRP3ASCcaspase1

The NLRP3-ASC-caspase-1 inflammasome is a cytosolic multiprotein complex that detects cellular stress and danger signals to trigger innate immune responses. In most cells, including macrophages, NLRP3 serves as the sensor, ASC acts as an adaptor, and pro-caspase-1 is the effector protease. Activation of this complex leads to the maturation of inflammatory cytokines and a form of programmed cell death called pyroptosis.

NLRP3 contains a pyrin domain (PYD) for partner interactions, a nucleotide-binding and oligomerization domain (NACHT), and leucine-rich repeats (LRRs) that regulate activation. ASC contains a PYD and a caspase recruitment domain (CARD). Upon sensing stimuli such as potassium efflux, mitochondrial damage, reactive oxygen species, extracellular ATP, or crystalline substances, NLRP3 oligomerizes and recruits ASC via PYD–PYD interactions. ASC then recruits pro-caspase-1 through CARD–CARD interactions, promoting autoproteolytic activation of caspase-1. The active caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature cytokines and also cleaves gasdermin D, whose N-terminal fragment forms membrane pores that drive pyroptotic cell death.

Activation typically requires two signals: a priming step that upregulates NLRP3 and pro-IL-1β, often via NF-κB, and an activation step from sterile or infectious stimuli. Regulation occurs at multiple levels, including transcriptional control, post-translational modifications, and negative regulators. Dysregulation is linked to autoinflammatory diseases such as CAPS and contributes to pathologies like gout, atherosclerosis, and metabolic disorders. Therapeutic approaches target the inflammasome itself (for example, NLRP3 inhibitors) or downstream effectors such as caspase-1 and IL-1β.