Alternative inflammasome activation enables IL-1β release from living cells

Classical modes of NLRP3 activation entail a priming step that enables its activation (signal 1) and a potassium effluxdependent activation signal (signal 2) that triggers pyroptosome formation and pyroptosis, a lytic cell death necessary for IL-1 beta release. Opposing to that, human monocytes engage an alternative NLRP3 inflammasome pathway in response to LPS that proceeds in the absence of signal 2 activation and enables IL-1 beta secretion without pyroptosis. This specifically relies on Caspase-8 to propagate signaling to NLRP3, leading to inflammasome activation in absence of pyroptosome formation. Here, we summarize the current knowledge about alternative inflammasome activation, discuss potential extensions of this signaling entity beyond LPS-dependent activation, speculate about its role in tissue homeostasis and sterile inflammation and highlight the implications of pyroptosis-independent IL-1 beta secretion.