Nlrp3: an immune sensor of cellular stress and infection

Abstract

Innate immune cells rely on pathogen recognition receptors such as the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family to mount an appropriate immune response against microbial threats. The NLR protein Nlrp3 senses microbial ligands, endogenous danger signals and crystalline substances in the cytosol to trigger the assembly of a large caspase-1-activating protein complex termed the Nlrp3 inflammasome. Autoproteolytic maturation of caspase-1 zymogens in the Nlrp3 inflammasome leads to maturation and extracellular release of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. Gain-of-function mutations in the NOD domain of Nlrp3 are associated with auto-inflammatory disorders characterized by skin rashes and prolonged episodes of fever. In addition, decreased Nlrp3 expression was recently linked with susceptibility to Crohn's disease in humans. In this review, we discuss recent developments on the role of the Nlrp3 inflammasome in innate immunity, its activation mechanisms and the auto-inflammatory disorders associated with deregulation of Nlrp3 inflammasome activity.

Figure 1

Structural organization of Nlrp3. The human cias1 gene encoding Nlrp3 is localized on chromosome 1q44. The positions of the neighboring genes encoding members of the olfactory receptor family 2 (or2b11, or2w5, or2wc3) and the zinc finger protein ZNF496 is shown to scale. Nlrp3 is produced from 9 coding exons (shown as purple bars), of which the first and last also encode the 5’ and 3’ untranslated regions, respectively (shown as white bars). Nlrp3 is expressed as a protein of 1036 amino acids consisting of an N-terminal pyrin domain, a central NACHT domain and 12 C-terminal LRR motifs. The positions of the CINCA- FCAS- and MWS-associated point mutations in Nlrp3 are indicated.

Figure 2

Overview of Nlrp3 signalling pathways. Assembly and activation of caspase-1 within the cytosolic Nlrp3 inflammasome complex is induced by several stimuli including binding of ATP to the purinergic receptor P2X₇, the ionophores nigericin and maitotoxin, β-amyloid and crystalline substances. Nlrp3 has been proposed to sense potassium efflux, the generation of ROS by the NADPH oxidase complex and lysosomal membrane disruption in response to these stimuli. Once activated in the Nlrp3 inflammasome, caspase-1 cleaves its substrates IL-1β, IL-18 and caspase-7 into the biologically active forms.