Figure 3.

NLRP3 is a cytosolic protein complex. It triggers the cleavage and activation of caspase-1, which is responsible for the cut and activation of pro-inflammatory cytokines (IL-1β and IL-18). Moreover, it causes the cut and the oligomerization of GSDRM monomers at the plasma membrane level, forming a pore to release IL-1β and IL-18, starting the pro-inflammatory signalling cascade and the pyroptotic cell death. The NLRP3 inflammasome induction requires the coexistence of two signals. The “first signal or priming” (on the left) is carried out by PAMPs, leading to the transcriptional upregulation of NLRP3 to induce the inflammasome component’s transcription. The “second signal” (in the centre) is activated by multiple upstream signalling events (e.g., ion fluxes, lysosomal disruption, and mtDNA release upon mitochondrial damage), and it is responsible for NLRP3 inflammasome activation. mtDNA release in the cytosol can also trigger the activation of cGAS-STING pathway (on the right). cGAS binds DNA in the cytosol and synthetizes GMP-AMP (cGAMP) from ATP and GTP. cGAMP binds STING located in ER membrane. Activated STING then recruits and activates TBK and IRF3, which leads to the production of type I interferons and other pro-inflammatory cytokines.