tlr-priming-signal → nlrp3-pro-il1b-upregulated — via NF-κB-driven transcription (signal 1). NLRP3 activation requires two signals. Signal 1 (priming) is typically a TLR/NF-κB stimulus that transcriptionally upregulates NLRP3 itself and pro-IL-1β — neither present at rest. This two-step requirement is a safety catch preventing inadvertent release of the potent cytokine IL-1β.
danger-signal → nlrp3-activation — via crystals + ATP + reactive oxygen → NLRP3 conformation (signal 2). Signal 2 (activation) is a diverse set of danger signals — ATP, pore-forming toxins, crystals (urate, cholesterol, silica), and ionic flux (notably K⁺ efflux) — that trigger NLRP3 to oligomerize and nucleate the inflammasome. The breadth of activators is why NLRP3 is central to so many sterile inflammatory diseases.
nlrp3-activation → caspase-1-activation — via NLRP3 + ASC + procaspase-1 oligomerization → caspase-1 autoactivation. Assembled NLRP3 recruits the adaptor ASC, which clusters and activates caspase-1 by induced proximity. This is the catalytic core of the inflammasome — converting danger recognition into an active protease, and the step targeted by direct NLRP3 inhibitors (MCC950) in development.
caspase-1-activation → il-1beta-secretion — via cleaves pro-IL-1β to mature IL-1β + GSDMD → pyroptotic pore. Active caspase-1 cleaves pro-IL-1β (and pro-IL-18) to their mature forms and cleaves gasdermin D to drive their release (and pyroptosis). IL-1β is a potent pyrogenic, pro-inflammatory cytokine — which is why IL-1 blockade (anakinra, canakinumab) treats inflammasome-driven diseases.