The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

Abstract

The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer's disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.

Keywords: Ionic flux; Lysosomal damage; Mitochondrial dysfunction; NLRP3 inflammasome; NLRP3 regulators; Post-translational modification; Priming; ROS.

Figure 1

A Two-Signal Model for NLRP3 Inflammasome Activation. The priming signal (signal 1, left) is provided by microbial components or endogenous cytokines, leading to the activation of the transcription factor NF-κB and subsequent upregulation of NLRP3 and pro-interleukin-1β (pro-IL-1β). Caspase-8 and FAS-mediated death domain protein (FADD), and NOD1/2 are involved in the priming step by regulating the NF-κB pathway. NLRP3 undergoes post-translational modifications that license its activation. The activation signal (signal 2, right) is provided by a variety of stimuli including extracellular ATP, pore-forming toxins, RNA viruses, and particulate matter. Multiple molecular or cellular events, including ionic flux, mitochondrial dysfunction and reactive oxygen species (ROS) generation, and lysosomal damage, have been shown to activate the NLRP3 inflammasome. BRCC3, BRCA1/BRCA2-containing complex subunit 3; IL-1R, IL-1β receptor; JNK1, JUN N-terminal kinase 1; PKD, protein kinase D; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor.

Figure 2

Mechanism of Activation for the Non-Canonical and Alternative NLRP3 Inflammasome Pathways. Non-canonical NLRP3 inflammasome activation (left) is induced by LPS internalization into the cytosol by transfection or infection. Caspase-11/4/5 induces pyroptosis through the cleavage of GSDMD. This process also activates pannexin-1 through caspase-11 to release ATP and induce K⁺ efflux, which drives NLRP3 inflammasome assembly and release of IL-1β. The alternative NLRP3 inflammasome (right) is activated in human monocytes in response to LPS and requires receptor-interacting serine/threonine-protein kinase 1 (RIPK1), FADD, and caspase-8 for its activation. This pathway is K⁺ efflux independent and does not induce pyroptosis.

Figure 3

Post-translational Modifications and Regulators of NLRP3. NLRP3 is regulated via phosphorylation (P), ubiquitination (Ub), sumolyation (S), and s-nitrosylation (SN) through post-translational modifications. Post-translational modifications that positively affect NLRP3 activation are listed on the left and those that negatively act on NLRP3 to inhibit its activation are listed in the middle. Interacting partners of NLRP3 are listed on the right. ARIH2, ariadne homolog 2; BRCC3, BRCA1/BRCA2-containing complex subunit 3; FBX12, F-box/LRR-repeat protein 2; FBXO3, F-box only protein 3; JNK1, JUN N-terminal kinase 1; MAPL, mitochondrial-anchored protein ligase; MARCH7, membrane-associated RING finger protein 7; NO, nitric oxide; PKA, protein kinase A; PKD, protein kinase D; PP2A, phosphatase 2A; PTPN22, protein tyrosine phosphatase non-receptor 22; SENP6/7, sentrin/SUMO-specific proteases. GBP5, guanylate-binding protein 5; Hsp90, heat-shock protein 90; MARK4, microtubule-affinity regulating kinase 4; MIF, macrophage migration inhibitory factor; NEK7, NIMA-related kinase 7; PKR, double-stranded RNA-dependent protein kinase; STG1, suppressor of the G2 allele of skp1; TXNIP, thioredoxin-interacting protein.