The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Abstract

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

Figure 1 |. NLRP3 inflammasome priming and activation.

The signal 1 (priming, left) is provided by activation of cytokines or pathogen-associated molecular patterns (PAMPs), leading to the transcriptional upregulation of canonical and non-canonical NLRP3 inflammasome components. Signal 2 (activation; right) is provided by any of numerous PAMPs or damage-associated molecular patterns (DAMPs), such as particulates, crystals and ATP, that activate multiple upstream signaling events. These include K+ efflux, Ca+ flux, lysosomal disruption, mitochondrial reactive oxygen species (mtROS) production, the relocalization of cardiolipin to the outer mitochondrial membrane and the release of oxidized mtDNA (Ox-mtDNA), followed by Cl− efflux. RNA viruses activate NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) through mitochondrial antiviral signaling protein (MAVS) on the mitochondrial outer membrane. Formation of the inflammasome activates caspase 1, which in turn cleaves pro-IL-1β and pro-IL-18. Gasdermin D (GSDMD) is also cleaved and inserts into the membrane, forming pores and inducing pyroptosis. Upon detection of cytosolic lipopolysaccharide (LPS), caspases 4, 5 and 11 are activated and cleave GSDMD, triggering pyroptosis. CARD, caspase recruitment domain; CLIC, chloride intracellular channel protein; GlcNAc, N-acetylglucosamine; GSDMDNterm, GSDMD amino-terminal cell death domain; HK , hexokinase; IFNAR , IFNα/β receptor ; IL-1R1, IL-1 receptor type 1; LRR , leucine-rich repeat; MDP, muramyl dipeptide; NEK7 , NIMA-related kinase 7; NF-κB, nuclear factor-κB; P2X7 , P2X purinoceptor 7; PtdIns4P, phosphatidylinositol-4-phosphate; PYD, pyrin domain; ROS, reactive oxygen species; TLR , Toll-like receptor ; TNF, tumor necrosis factor ; TNFR , tumor necrosis factor receptor ; TWIK2, two-pore domain weak inwardly rectifying K+ channel 2.

Figure 2 |. Post-transcriptional modifications of NLRP3.

NLRP3 is regulated by phosphorylation (P), ubiquitylation (Ub) and sumoylation (S). Activating regulatory modifications are listed on the left and those that inhibit NLRP3 activation are on the right. Amino acid residues in both human and mouse NLRP3 are listed for phosphorylation, whereas ubiquitylation and sumoylation refer only to the murine protein residues. PP2A, protein phosphatase 2A; JNK1, JUN N-terminal kinase 1; PKD, protein kinase D; BRCC3, BRCA1/BRCA2-containing complex subunit 3; PTPN22, tyrosine-protein phosphatase non-receptor type 22; MUL1, E3 SUMO-protein ligase MUL1; PKA, protein kinase A; ARIH2, E3 ubiquitin-protein ligase ARIH2; TRIM31, tripartite motif-containing protein 31; FBXL2, F-box/LRR-repeat protein 2; MARCH7, membrane-associated RING finger protein 7; PYD, pyrin domain; NACHT, NAIP, CIITA, HET-E and TP1 shared domain; LRR, leucine-rich repeat domain.