Regulation and functions of the NLRP3 inflammasome in RNA virus infection

Abstract

Virus infection is one of the greatest threats to human life and health. In response to viral infection, the host's innate immune system triggers an antiviral immune response mostly mediated by inflammatory processes. Among the many pathways involved, the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome has received wide attention in the context of viral infection. The NLRP3 inflammasome is an intracellular sensor composed of three components, including the innate immune receptor NLRP3, adaptor apoptosis-associated speck-like protein containing CARD (ASC), and the cysteine protease caspase-1. After being assembled, the NLRP3 inflammasome can trigger caspase-1 to induce gasdermin D (GSDMD)-dependent pyroptosis, promoting the maturation and secretion of proinflammatory cytokines such as interleukin-1 (IL-1β) and interleukin-18 (IL-18). Recent studies have revealed that a variety of viruses activate or inhibit the NLRP3 inflammasome via viral particles, proteins, and nucleic acids. In this review, we present a variety of regulatory mechanisms and functions of the NLRP3 inflammasome upon RNA viral infection and demonstrate multiple therapeutic strategies that target the NLRP3 inflammasome for anti-inflammatory effects in viral infection.

Keywords: NLRP3 inflammasome; RNA virus; inflammation; pyroptosis; therapeutic strategy.

Figure 1

Schematic diagram of the two signaling pathways warranted for activating the NLRP3 inflammasome. Two signals are needed for activating the NLRP3 inflammasome. The first is the priming signal: tumor necrosis factor (TNF) and lipopolysaccharide act on the cell surface receptors TNFR and Toll-like receptor (TLR) 4, which activate the nuclear factor- kappaB (NF-κB) pathway and induce gene expression to produce large amounts of pro-IL-1β, pro-IL-18, and NLRP3. The second is the activation signal: pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) induce the assembly and activation of the NLRP3 inflammasome. There are three main DAMP models: (1) ionic flux model, (2) reactive oxygen species (ROS) production, and (3) lysosomal damage. The activated NLRP3 inflammasome activates caspase-1, pro-IL-1β, and pro-IL-18 to produce active IL-1β and IL-18 under the action of active caspase-1, finally releasing them outside the cell. In addition, activated caspase-1 can also cleave GSDMD to N-GSDMD and liberate them to insert into membrane and form the pyroptotic pores. The mature IL-1β and IL-18 release out of the cell together with cell content through GSDMD-pores to induce pyroptosis.

Figure 2

Schematic diagram of the mechanism by which SARS-CoV-2 activates the NLRP3 inflammasome. SARS-CoV-2 infection may activate the NLRP3 inflammasome in the following ways: (1) one of the subunits of the spike glycoprotein S1 can release proinflammatory cytokines via mechanisms involving the activation of the NF-κB pathway. (2) The E protein of SARS-CoV-2 can cause lysosomal damage to release a large amount of Ca²⁺, thereby activating the NLRP3 inflammasome. (3) The N viral protein interact with NLRP3 to promote inflammasome assembly; the complement cascade induced by the N protein–MBL-MASP2 axis may lead to the activation of the NLRP3 inflammasome via the different functions of C3a, C5a, and membrane attack complex (MAC). (4) ORF3a primes the inflammasome via NF-κB-mediated transcriptional activation of pro-IL-1β. Furthermore, ORF3a activates the NLRP3 inflammasome via K⁺ efflux and NEK7. The activated NLRP3 inflammasome can activate transcription of pro-IL-1β and pro-IL-18 and produce mature IL-1β and IL-18.

Figure 3

Schematic diagram of the mechanism by which Zika virus activates the NLRP3 inflammasome. After the Zika virus invades and infects the cells, it activates the NF-κB pathway, inducing gene expression to produce pro-IL-1β and NLRP3. (1) The NS5 protein interacts with NLRP3 to promote the assembly of the NLRP3 inflammasome. The induced mitochondrial ROS leads to pro-caspase-1 cleavage and IL-1β release (2): The NS3 protein inhibits the activation of the NLRP3 inflammasome by cleaving NLRP3, decreasing caspase-1 activation and mature IL-1β secretion.