Mobilization of Inflammasome Components for Anaphylactic Degranulation by Mast Cells

Abstract

Abstract Inflammasome components, NLRP3 and ASC are cytosolic proteins which upon sensing endotoxins/danger cues, form multimeric complexes to process IL-1β for secretion. Here, we reveal that the iconic IgE/antigen (Ag) mediated mast cell (MC) degranulation, an activity independent of IL-1β secretion is mediated by NLRP3 and ASC. IgE/Ag stimulated NEK7 and Pyk2 kinases induce NLRP3 and ASC deposition on granules forming a distinct protein complex (granulosome) to chaperone granules to the cell surface. MCs deficient in NLRP3 or ASC fail to form granulosomes, degranulate poorly in vitro and fail to evoke systemic anaphylaxis in mice. IgE/Ag-triggered anaphylaxis is prevented with an NLRP3 inhibitor. Interestingly, in endotoxin primed MCs, pro-IL-1β is rapidly packaged into granules after IgE/Ag stimulation and processed within granule remnants by proteases after degranulation, causing lethal anaphylaxis in mice. During IgE/Ag mediated degranulation of endotoxin primed MCs, granulosomes promote degranulation combined with exteriorization and processing of IL-1β resulting in severe inflammation.