The NLRP3 inflammasome: activation and regulation

Abstract

The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a cytoplasmic supramolecular complex that is activated in response to cellular perturbations triggered by infection and sterile injury. Assembly of the NLRP3 inflammasome leads to activation of caspase-1, which induces the maturation and release of interleukin-1β (IL-1β) and IL-18, as well as cleavage of gasdermin D (GSDMD), which promotes a lytic form of cell death. Production of IL-1β via NLRP3 can contribute to the pathogenesis of inflammatory disease, whereas aberrant IL-1β secretion through inherited NLRP3 mutations causes autoinflammatory disorders. In this review, we discuss recent developments in the structure of the NLRP3 inflammasome, and the cellular processes and signaling events controlling its assembly and activation.

Keywords: Golgi; metabolism; mitochondria; phosphorylation; potassium efflux; ubiquitination.

Figure 1.. Components of the NLRP3 inflammasome and proposed model of NLRP3 activation.

Components of NLRP3 inflammasome: NLRP3, ASC, caspase-1 and NIMA-related kinase 7 (NEK7) (top left). The inactive form of NLRP3 (human 10-mer, mouse 12–16 mer) (bottom left). Only four of the NLRP3 monomers are displayed for simplicity to illustrate interactions among leucine-rich repeats (LRRs). The hypothetical model of the active NLRP3 inflammasome (bottom right). For simplicity, only two of the pyrin domains (PYDs) of NLRP3 interacting with the PYDs of ASC are shown. Abbreviations GSDMD, gasdermin D; IL, interleukin.

Figure 2.. Cellular events leading to NLRP3 inflammasome activation.

The activation signal is provided by an array of stimuli including particulate matter, ATP, pore-forming toxins and RNA viruses. Particulate matter via lysosomal membrane damage and viral RNA through mitochondrial antiviral signaling protein (MAVS) induce K⁺ efflux, which also occurs upon stimulation with most NLRP3 stimuli. As an exception, imiquimod (IMQ) activates NLRP3 without inducing K⁺ efflux. NIMA-related kinase 7 (NEK7) functions downstream of K⁺ efflux. NEK7 is shown associated with the centrosome (in green). The binding of receptor for activated C kinase 1 (RACK1) to NEK7 and NLRP3 is required for inflammasome activation, but the mechanism remains poorly understood. Mitochondrial ETC sustains NLRP3 activation via phosphocreatine-dependent generation of ATP. Dysfunction of the mitochondria is associated with the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) into the cytosol as well as localization of cardiolipin to the outer mitochondrial membrane which may promote NLRP3 activation. Upon stimulation, NLRP3 transition to membranes of the dispersed trans-Golgi network (TGN) or endosomes which may be important for inflammasome activation. CLIC, chloride intracellular channel; ER, endoplasmic reticulum; ETC, electron transport chain; ox-mtDNA, oxidized; PI4P, phosphatidylinositol 4-phosphate; P2X7, purinergic receptor P2X 7; TWIK2, two-pore domain weak inwardly rectifying K⁺ channel 2. This figure was created with resources from BioRender.com