Role of the nlrp3 inflammasome in microbial infection

Abstract

The intracellular Nod-like receptor Nlrp3 has emerged as the most versatile innate immune receptor because of its broad specificity in mediating immune response to a wide range of microbial or danger signals. Nlrp3 mediates assembly of the inflammasome complex in the presence of microbial components leading to the activation of caspase-1 and the processing and release of the pro-inflammatory cytokines IL-1β and IL-18. In this review, we give an update on the recent literature examining the role of Nlrp3 inflammasome in response to fungal, bacterial, and viral infections.

Keywords: IL-18; IL-1β; NLR; Nlrp3; caspase-1; inflammasome.

Figure 1

Signaling mechanisms proposed for Nlrp3 inflammasome activation. Extracellular and intracellular pathogen-associated molecular patterns (PAMPs) are sensed by toll-like receptors (TLRs; first signal) leading to NF-κB activation and transcription of cytokines. Additionally, NF-κB is also proposed to up-regulate Nlrp3 expression, which might be a limiting factor for inflammasome assembly. A wide range of pathogens trigger Nlrp3 inflammasome activation. The physiological insults resulting from exposure to these PAMPs can be narrowed down to a few mechanisms that drive Nlrp3 activation. These mechanisms include K⁺ efflux, lysosomal damage and reactive oxygen species (ROS) production (second signal). Activation of P2X7R by ATP results in membrane pores that allow K⁺ efflux and entry of extracellular factors into the cytoplasm resulting in Nlrp3 activation. Phagocytosis of certain pathogenic microbes leads to rupture of lysosomes thereby releasing cathepsin B into the cytoplasm and causing Nlrp3 activation. Generation of ROS downstream of microbial infection has also been proposed to trigger Nlrp3. Nlrp3 inflammasome assembly consisting of the adaptor molecule Asc and pro-caspase-1 leads to caspase-1 activation, which results in processing and secretion of cytokines IL-1β and IL-18.