Figure 3.

Canonical and non-canonical NLRP3 inflammasome activation. Canonical NLRP3 inflammasome activation requires two steps: the priming step and the activation step. In the priming step, TLR stimulation induces the transcription and expression of NLRP3 and pro-IL-1 through NF-κB. Subsequently, various PAMPs and DAMPs induce the activation step by initiating numerous molecular and cellular events, including K+ efflux, mitochondrial dysfunction, reactive oxygen species (ROS) release, and lysosomal disruption. The NLRP3-dependent self-cleavage and activation of pro-caspase-1 self-cleavage and activation leads to the maturation of the pro-inflammatory cytokine’s interleukin 1 (IL-1) and interleukin 18 (IL-18). Additionally, gasdermin D (GSDMD) is cleaved by activated caspase-1, releasing its N-terminal domain, which then integrates into the cell membrane to create pores. These pores allow the release of cellular contents, including IL-1 and IL-18, and trigger pyroptosis, a form of inflammatory cell death. The non-canonical NLRP3 inflammasome is activated by cytosolic LPS, which directly interacts with caspase-4/5 in human (caspase-11 in mice). This interaction results in the autoproteolysis and activation of these caspases. The activated caspases subsequently open the pannexin-1 channel, allowing ATP release from the cell and activating the P2X7R, causing K+ efflux, canonical NLRP3 activation and the maturation of IL-1 and IL-18. In addition, activated caspase-4/5-11 cleaves GSDMD to cause membrane pore formation and pyroptosis, contributing to the release of IL-1 and IL-18.