Fig. 2

Mechanisms of canonical and non-canonical activation of NLRP3. The canonical pathway involves TLR signaling, which induces the transcription of IL-1β, IL-18, and NLRP3 through NF-κB pathway. The non-canonical pathway involves stimuli such as LPS, which require caspase-11 for caspase-1 activation. Upon sensing danger signals, NLRP3 assembles into a multiprotein complex with the adaptor protein ASC and recruits caspase-1. Activated caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature forms, which are then secreted to initiate an immune response. Non-canonical pathway of TLR signaling for NLRP3 involves the activation of caspase-11 by cytosolic LPS from Gram-negative bacteria. Caspase-11 activation leads to the cleavage of gasdermin D, which forms pores in the cell membrane and triggers pyroptosis. Caspase-11 activation also induces the opening of the pannexin-1 channel, which leads to K+ efflux and NLRP3 inflammasome activation. The activation of P2X7 by ATP released from the pannexin-1 channel also contributes to pyroptosis. Signal 1 (priming) involves the transcriptional upregulation of NLRP3, pro-IL-1β, and pro-IL-18 by TLR, TNFR, and IL-1R signaling pathways. Signal 2 (activation) results in the cleavage and release of mature IL-1β and IL-18. It can be triggered by various stimuli, including extracellular ATP, pore-forming toxins, K+ efflux, lysosomal and mitochondrial damage, crystal deposition such as monosodium urate (MSU), Calcium pyrophosphate deposition (CPPD), alum, and cholesterol crystals, and reactive oxygen species (ROS)