Figure 1.

Schematic illustration of selected inflammasome components and mechanism of NLRP3 activation. (A) Shown here is the composition of NLRP3 and absent in melanoma-2 inflammasome sensors as well as the components ASC and caspase-1. (B) NLRP3 inflammasomes activation involves a two-step process: priming and assembly. Signal 1 (priming) is provided by nuclear factor-κB-dependent transcription of pro-interleuking-1β and NLRP3, either through the activation of TLRs or nucleotide-binding oligomerization domain 2 (NOD2) by microbial molecules or endogenous cytokines. The second signal is provided by stimuli that specifically activate NLRP3 and lead to NLRP3 oligomerization, caspase-1 activation followed by the maturation and release of IL-1β and IL-18. Three separate phenomena had been associated with NLRP3 activation. Event 1: ATP mediated ionic flux and intracellular potassium depletion mediated by ATP binding to ligand-gated ion channels P2X₇R. Event 2: cathepsin release following destabilization of lysosomal membrane by sterile particulates, such as silica, asbestos, and cholesterol crystals. Event 3: generation of ROS and cytoplasmic release of mitochondrial DNA following major cellular stress and mitochondrial damage. Abbreviations: ATP, adenosine triphosphate; AIM2, absent in melanoma-2; ASC, apoptosis-associated speck-lick protein containing a CARD; CARD, caspase-activation and recruitment domain; HIN-200, hematopoietic interferon-inducible nuclear proteins with a 200-amino-acid repeat; IL-1β/IL-18, interleukin 1β/18; LPS, lipopolysaccharide; LRR, leucine-rich repeats; NBD/NACHT, nuclear binding domain; NF-κB, nuclear factor-κB; NLRP3, NLR family pyrin domain-containing; NLR, nucleotide-binding domain and leucine-rich repeat receptors; NOD2, nucleotide-binding oligomerization domain 2; PYD, pyrin domain; ROS, reactive oxygen species; TLRs, toll-like receptors.