Abstract：
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.
摘要：
炎症体成分NLRP3和ASC是胞质蛋白，一旦感知到内毒素或危险信号，形成多聚体复合物以处理白细胞介素（IL）-1β用于分泌。在这里，我们发现抗原（Ag）触发的IgE致敏肥大细胞（MC）的脱颗粒是由NLRP3和ASC介导的。IgE-Ag刺激MCs中的NEK7和Pyk2激酶，以诱导NLRP3和ASC在颗粒上的沉积，并形成独特的蛋白质复合物（颗粒体），将颗粒陪伴到细胞表面。缺乏NLRP3或ASC的MC不形成颗粒体，体外脱粒效果较差，并且不会引起小鼠的全身过敏反应。NLRP3抑制剂可预防IgE-Ag引发的过敏反应。在内毒素引发的MC中，pro-IL-1β在IgE-Ag刺激后迅速包装成颗粒，并在脱粒后通过蛋白酶在颗粒残余物中处理，在小鼠中引起致命的过敏反应。在IgE-Ag介导的内毒素引发的MC脱粒过程中，颗粒体促进脱粒，结合IL-1β的外化和加工，导致严重的炎症。
