The NLRP3 inflammasome is the main platform that converts DAMP recognition into secreted cytokine. It requires two signals. The first, a priming signal, activates NF-kB and raises the levels of NLRP3 and pro-IL-1beta. The second, an activation signal, is usually a potassium efflux, a lysosomal rupture, or a burst of mitochondrial reactive oxygen species. When that second signal arrives, NLRP3 oligomerizes and recruits the adaptor ASC, which nucleates filaments of pro-caspase-1. Proximity forces pro-caspase-1 to cleave itself into active caspase-1. Active caspase-1 then does two things: it cleaves pro-IL-1beta and pro-IL-18 into their mature secreted forms, and it cleaves gasdermin D. The gasdermin D N-terminal fragment inserts into the plasma membrane and forms pores. Those pores allow IL-1beta and IL-18 to exit and, if enough pores form, drive a lytic form of cell death called pyroptosis. The output is therefore both a cytokine signal and, at high intensity, a further release of DAMPs.
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Watch the two signals arrive in sequence. The first signal is priming: NF-kB raises NLRP3 and pro-IL-1beta, but nothing assembles yet. The second signal is the trigger, usually potassium efflux or mitochondrial reactive oxygen species. Only then does NLRP3 oligomerize and recruit ASC, which forms a single concentrated speck. That speck brings pro-caspase-1 molecules close enough to cleave each other into active caspase-1. Active caspase-1 then cuts pro-IL-1beta and pro-IL-18 into their mature forms, and it also cuts gasdermin D. The gasdermin D fragment punches pores in the membrane, so the cytokines exit. If enough pores form, the cell lyses and releases more DAMPs, which is why intense inflammasome activation amplifies rather than resolves the signal.
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