Neutrophils use a novel NLRP3 inflammasome-independent mechanism to release bioactive IL-1β in response to lysosomal disruption

Abstract IL-1β is an inflammatory cytokine mainly secreted by myeloid cells in response to infection or sterile tissue damage. Non-canonical secretion of from macrophages downstream activated NLRP3/caspase-1 inflammasomes the best-characterized model; this mediated caspase-1 cleavage GSDMD allowing N-GSDMD form pores plasma membrane that act as conduits for release and inducers pyroptosis a lytic cell death. The NLRP3 initiator acts sensor perturbed cellular homeostasis including decreased cytosolic [K+]. In macrophages, K+ efflux activation also triggered agents disrupt lysosomal integrity. While neutrophils assemble competent bioactive via GSDMD-dependent mechanisms, they resist formation progression pyroptosis. We tested whether lysosome disrupting stimuli would phenocopy macrophage mechanisms secrete manner. Surprisingly, our data indicate lysosome-disrupting induce mature undergo rapid death independently inflammasome assembly activity with only partial dependence on GSDMD. Ongoing studies testing effects serine protease inhibitors support mechanism which accumulation multiple proteases stored lysosome-like azurophilic granules coordinately canonical directly cleave proIL-1β part novel neutrophil-specific signaling disruption-induced processing export IL-1β. P01-AI141350 R01-EY014362 R21-EY032662