PMC

The inflammasome. Stimulation of AIM2, RIG-I or an NLR by its cognate agonist promotes inflammasome activation and heptameric oligomerization. The active inflammasome induces caspase-1 activation, allowing processing of pro-IL-1β and pro-IL-18 into their mature forms

The human NLR family and inflammasome-associated proteins. There are 22 human NLRs characterized by a central nucleotide-binding domain (NB). The NLR family can be further classified into four subfamilies, depending on the protein's N-terminal domain. CARD and PYD domains enable interaction with caspase-1 or the adaptor ASC, allowing assembly of the inflammasome. The pattern-recognition receptors (PRRs) AIM2 and RIG-I are also capable of forming inflammasomes

Inflammasome activation and regulation. The mitochondria are at the center of inflammasome activation and regulation. Mitochondrial ROS leads to transcriptional induction of pro-IL-1β and NLRP3 through MAPKs, NF-κB and HIF-1, priming the cell for inflammasome activation. The NLRs are bound by Hsp90 and SGT1, which maintain them in an activation competent state, upon which oligomerization with the adaptor ASC and caspase-1 forms a functional inflammasome, leading to the cleavage and release of IL-1β and IL-18. Caspase-5 is associated with the NLRP1 inflammasome, which is activated by MDP and negatively regulated by BCL-XL and BCL-2. Mitochondrial outer membrane permeabilization (through voltage-dependent anionic channels and inhibited by BCL-2) is essential for NLRP3 inflammasome activation. NLRX1, which resides within the mitochondria, is reported to inhibit MAVS- and TRAF6-mediated signaling, and to modulate ROS generation. The phagocytosis of large crystals leads to lysosomal rupture followed by release of cathepsin B into the cytosol and NLRP3 inflammasome activation. Microbial toxins and the ATP ionotropic P2X7 purinergic receptor that functions as an ATP-activated cation channel lead to potassium efflux, which activates the NLRP3 inflammamsome. The saturated fatty acid palmitate inhibits AMPK, which leads to reduced mitophagy and increased ROS production. Palmitate is also metabolized into ceramide, which is detected by NLRP3. High concentrations of glucose also activate NRLP3 through binding of TXNIP. Deregulated activation of the NLRP3 inflammasome has been linked to CAPS, gout, atherosclerosis and type 2 diabetes