Figure 1. Activation of the NLRP3 inflammasome.

The NLRP3 inflammasome requires a two-step process to produce the pro-inflammatory cytokines IL-1β and IL-18. The first step (called the priming signal- depicted on the left) involves receptor-mediated activation of the transcription factor NF-κB which increases transcripts of pro-IL-1β and pro-IL-18 along with components of the inflammasome machinery including caspase-1 and NLRP3. The second step (called the activation signal- depicted on the right) involves various triggers for the assembly of the inflammasome complex including ATP, potassium efflux, and crystalline particles such as cholesterol crystals, mitochondrial ROS, and lysosomal destabilization. Oligomerization of the inflammasome components NLRP3 and ASC leads to recruitment and activation of Caspase-1 which in turn, 1) cleaves the precursor forms of IL-1β and IL-18 to their active and releasable forms, and 2) cleaves GSDMD to its active membrane pore-forming fragment GSDMD-N facilitating pyroptosis.

Abbreviations: NLRP3 (nucleotide‐binding domain, leucine‐rich repeat–containing receptor family, pyrin domain‐containing 3), IL-1β and IL-18 (interleukin-1β and −18), ASC (Apoptosis-associated speck-like protein containing a CARD), ATP (adenosine triphosphate), ROS (reactive oxygen species), GSDMD (Gasdermin D), GSDMD (Gasdermin N)