NLRP3 inflammasome and NF-κB signaling pathway (NLRP3/NF-κB pathway)

The NLRP3 inflammasome and NF-κB signaling pathway is a central mediator of the innate immune response, integrating cellular stress signals to drive inflammation (Nature Reviews Immunology, 2019). The pathway operates via a two-signal model: a 'priming' signal mediated by the NF-κB transcription factor that induces the expression of NLRP3 and pro-IL-1β, and an 'activation' signal that triggers the assembly of the NLRP3 inflammasome complex (Science, 2019). This complex, consisting of the NLRP3 sensor, ASC adapter, and caspase-1, facilitates the proteolytic maturation of IL-1β and IL-18 and initiates gasdermin D-mediated pyroptotic cell death (Journal of Clinical Investigation, 2018). Chronic overactivation of this axis is a hallmark of numerous inflammatory, metabolic, and neurodegenerative diseases, including gout, atherosclerosis, and Alzheimer's disease (Cell, 2018). Pharmacological targeting of this pathway involves small molecules that either inhibit the NF-κB priming step or directly block NLRP3 assembly and activity (Pharmacological Reviews, 2020). Such interventions aim to selectively suppress pathological inflammation while maintaining essential immune surveillance (Nature Medicine, 2015).

Other names

NLRP3-NF-κB axisNLRP3 inflammasome signalingNF-kappaB/NLRP3 pathwayCryopyrin inflammasome pathwayNLRP3-caspase-1-IL-1β axis

Inhibition of NLRP3 ATPase activity to prevent conformational changes required for oligomerization, blockade of IκB kinase (IKK) to prevent NF-κB nuclear translocation and subsequent priming, and inhibition of caspase-1 activity to prevent the maturation of pro-inflammatory cytokines IL-1β and IL-18.