The inflammasome components NLRP3 and ASC are cytosolic proteins, which upon sensing endotoxins or danger cues, form multimeric complexes to process interleukin (IL)-1β for secretion. Here we found that antigen (Ag)-triggered degranulation of IgE-sensitized mast cells (MCs) was mediated by NLRP3 and ASC. IgE–Ag stimulated NEK7 and Pyk2 kinases in MCs to induce the deposition of NLRP3 and ASC on granules and form a distinct protein complex (granulosome) that chaperoned the granules to the cell surface. MCs deficient in NLRP3 or ASC did not form granulosomes, degranulated poorly in vitro and did not evoke systemic anaphylaxis in mice. IgE–Ag-triggered anaphylaxis was prevented by an NLRP3 inhibitor. In endotoxin-primed MCs, pro-IL-1β was 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 promoted degranulation, combined with exteriorization and processing of IL-1β, resulting in severe inflammation.

炎性体成分 NLRP3 和 ASC 是胞质蛋白，在感知内毒素或危险信号时，形成多聚体复合物来处理白细胞介素 (IL)-1β 进行分泌。在这里，我们发现抗原（Ag）触发的 IgE 致敏肥大细胞（MC）脱颗粒是由 NLRP3 和 ASC 介导的。IgE-Ag 刺激 MC 中的 NEK7 和 Pyk2 激酶，诱导 NLRP3 和 ASC 在颗粒上沉积，并形成独特的蛋白质复合物（颗粒体），将颗粒陪伴至细胞表面。NLRP3 或 ASC 缺陷的 MC 不形成颗粒体，体外脱颗粒效果较差，并且不会引起小鼠全身过敏反应。NLRP3 抑制剂可以预防 IgE-Ag 引发的过敏反应。在内毒素引发的 MC 中，IL-1β 前体在 IgE-Ag 刺激后迅速包装成颗粒，并在脱颗粒后被蛋白酶在颗粒残余物中加工，导致小鼠致命性过敏反应。在 IgE-Ag 介导的内毒素引发的 MC 脱颗粒过程中，颗粒体促进脱颗粒，并结合 IL-1β 的外化和加工，导致严重的炎症。