Reframing the link between metabolism and NLRP3 inflammasome: therapeutic opportunities

Abstract

Inflammasomes are multiprotein signaling platforms in the cytosol that senses exogenous and endogenous danger signals and respond with the maturation and secretion of IL-1β and IL-18 and pyroptosis to induce inflammation and protect the host. The inflammasome best studied is the Nucleotide-binding oligomerization domain, leucine-rich repeat-containing family pyrin domain containing 3 (NLRP3) inflammasome. It is activated in a two-step process: the priming and the activation, leading to sensor NLRP3 oligomerization and recruitment of both adaptor ASC and executioner pro-caspase 1, which is activated by cleavage. Moreover, NLRP3 inflammasome activation is regulated by posttranslational modifications, including ubiquitination/deubiquitination, phosphorylation/dephosphorylation, acetylation/deacetylation, SUMOylation and nitrosylation, and interaction with NLPR3 protein binding partners. Moreover, the connection between it and metabolism is receiving increasing attention in this field. In this review, we present the structure, functions, activation, and regulation of NLRP3, with special emphasis on regulation by mitochondrial dysfunction-mtROS production and metabolic signals, i.e., metabolites as well as enzymes. By understanding the regulation of NLRP3 inflammasome activation, specific inhibitors can be rationally designed for the treatment and prevention of various immune- or metabolic-based diseases. Lastly, we review current NLRP3 inflammasome inhibitors and their mechanism of action.

Keywords: NLRP3 inflammasome; metabolic regulation; mitochondrial dysfunction; mtROS; pyroptosis.

Figure 1

Structure of the components of the NLRP3 inflammasome. NLRP3 is composed of the N-ter PYD, NACHT and C-ter LRR. ASC is composed of theN-ter PYD and the C-ter CARD. Finally, caspase-1 is composed of the N-ter CARD, p20 (large catalytic subunit) and C-ter p10 (small catalytic subnit). The interdomain linker (IDL) binds p20 and p10 and is cleaved to process inactive zymogen pro-caspase-1 to active caspase-1. Oligomerization of NLRP3 and homotypic interactions PYD-PYD and CARD-CARD lead to the NLRP3 inflammasome assembly.

Figure 2

Model for NLRP3 activation by two-step process. Priming (step 1) licenses the cell for NLRP3 inflammasome activation. Certain PAMPs and cytokines (CK) bind to their receptors, e.g.: LPS/TLR4, TNF-α/TNFR or IL-1/IL-1R, leading to activation of NF-κB, which translocate into the nucleus and activates transcription of NLRP3, caspase-1, IL-1β and IL-18. Activation (step 2) starts with the sensing of danger signals, PAMPs and DAMPs, by NLRP3. These stimuli trigger the activation of NLRP3 inflammasome through K⁺ or Cl^- efflux, Ca²⁺ flux, lysosomal disruption, mitochondrial dysfunction and reactive oxygen species (ROS) generation, metabolic signals and trans-Golgi disassembly, and it seems that K⁺ efflux is the convergence point for the activation of NLRP3 inflammasome. NLRP3 inflammasome activation occurs through NLRP3 and ASC oligomerization and assembly. NLRP3 inflammasome recruits and activates pro-caspase-1. Caspase-1 cleaves and activates pro-IL-1β and pro-IL-18 and GSDMD. Proinflammatory CKs are released through GSDMD pore and pyroptosis. Ultimately, NLRP3 inflammasome signals for inflammation and cell death by pyroptosis.