Mechanism and Regulation of NLRP3 Inflammasome Activation

Abstract

Members of the nucleotide-binding domain and leucine-rich repeat (LRR)-containing (NLR) family and the pyrin and HIN domain (PYHIN) family can form multiprotein complexes termed 'inflammasomes'. The biochemical function of inflammasomes is to activate caspase-1, which leads to the maturation of interleukin 1 beta (IL-1β) and IL-18 and the induction of pyroptosis, a form of cell death. Unlike other inflammasomes, the NLRP3 inflammasome can be activated by diverse stimuli. The importance of the NLRP3 inflammasome in immunity and human diseases has been well documented, but the mechanism and regulation of its activation remain unclear. In this review we summarize current understanding of the mechanism and regulation of NLRP3 inflammasome activation as well as recent advances in the noncanonical and alternative inflammasome pathways.

Keywords: K(+) efflux; NLRP3 inflammasome; Nek7; alternative inflammasome; noncanonical inflammasome.

Figure 1

A two-signal model for NLRP3 inflammasome activation. Signal 1 (priming, left) is provided by microbial molecules or endogenous cytokines and leads to the upregulation of NLRP3 and pro-IL-1β through the activation of transcriptional factor NF-κB. Caspase-8 and FADD are involved in priming via the regulation of the NF-κB activation pathway. BRCC3 (a deubiquitinase) and IRAK1 regulate NLRP3 inflammasome activation independently of transcription. Signal 2 (activation, right) is provided by a plethora of stimuli, such as ATP, pore-forming toxins, viral RNA and particulate matter, and activates the NLRP3 inflammasome. A number of signaling events have been proposed as the key mechanism of NLRP3 activation. Most NLRP3 stimuli induce K⁺ efflux that is necessary and sufficient for NLRP3 activation. Ca²⁺ signaling is proposed to cause mitochondrial dysfunction and is implicated in NLRP3 inflammasome activation. Mitochondrial dysfunction-derived signals, such as reactive oxygen species (mtROS), oxidized mtDNA or externalization of phospholipid cardiolipin have also been suggested to mediate NLRP3 activation. Mitochondrial adaptor MAVS mediates NLRP3 activation induced by RNA viruses. Particulate matter activates NLRP3 through lysosomal rupture-induced K⁺ efflux and perhaps the release of cathepsins. Nek7 is an essential regulator of the NLRP3 inflammasome. TLR: Toll-like receptor; IL-1R: receptor for IL-1β; TNFR: receptor for tumor-necrosis factor; BRCC3: Lys-63-specific deubiquitinase BRCC36; FADD: FAS-associated death domain protein; IRAK1:Interleukin-1 receptor-associated kinase 1.

Figure 2

Mechanisms of activation for non-canonical and alternative NLRP3 inflammasomes. Non-canonical NLRP3 inflammasome activation (left side of the figure) is induced by Gram-negative bacteria. LPS is delivered into the cytosol through transfection or infection and activates caspase-11. Active caspase-11 triggers the opening of the pannexin-1 channel through cleavage, which induces the K⁺ efflux required for NLRP3 inflammasome activation and release of IL-1β. Caspase-11 activation also drives pyroptosis through the cleavage of gasdermin D. The gasdermin D N domain disrupts cellular functions by forming pores on the membrane. The activation of P2X7 by ATP released from the pannexin-1 channel also contributes to pyroptosis. The alternative NLRP3 inflammasome (right side of the figure) is activated in human monocytes in response to LPS. For this pathway, K⁺ efflux is dispensable, and molecules RIPK1, FADD and CASP8 are required, and no ASC speck formation or pyroptosis is induced.