Unraveling unconventional pathways: NLRP3 inflammasome signaling and IL-1β release in murine bone marrow derived mast cells (BMMC)

Activation of the NLRP3 inflammasome involves hierarchical activation and assembly of upstream protein complexes, ultimately releasing IL-1β – a proinflammatory cytokine implicated in many physiological and pathological responses. Previous studies utilized macrophages (Mf) as model myeloid cells for defining NLRP3 inflammasome biology and extrapolated these data to myeloid mast cell (MC) models. However, our studies indicate that murine BMMC regulate NLRP3 inflammasome signaling and IL-1β release via mechanisms distinct from those in Mf including: 1) release of IL-1β independent of Gasdermin (GSDM)-family pores; 2)  more efficacious NLRP3 priming by IL-33/ST2 versus LPS/TLR4 as ”signal 1” stimuli; 3) low efficacy  of ATP versus high efficacy of nigericin as “signal 2” stimuli for NLRP3 inflammasome assembly and IL-1β release, despite similar efficacies as  K⁺ efflux inducers^. These differences in efficacy track with the ability of ATP, but not nigericin, to serve as a robust MC degranulation stimulus, indicating functional crosstalk between exocytotic degranulation, NLRP3 activation, and IL-1β export in MCs. Our current studies suggest a non-canonical role for NLRP3 in the regulation of MC degranulation, in addition to its canonical role in MC inflammasome activation, potentially uncovering novel targets for therapeutic intervention in inflammatory and allergic disorders.