美国杜克大学Soman N. Abraham团队发现，肥大细胞的过敏性脱颗粒需要动员炎性小体组分。该项研究成果于2024年3月14日在线发表在《自然—免疫学》杂志上。

研究人员发现抗原（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刺激肥大细胞中的NEK7和Pyk2激酶，诱导NLRP3和ASC沉积在颗粒上，并形成一种独特的蛋白复合物（颗粒体），将颗粒体包裹到细胞表面。缺乏NLRP3或ASC的MC不会形成颗粒体，体外脱颗粒能力差，也不会诱发小鼠全身性过敏性休克。NLRP3抑制剂可预防IgE-Ag诱发的过敏性休克。

在内毒素诱导的MC中，白细胞介素（IL）-1β前体在IgE-Ag刺激后迅速包装成颗粒，脱颗粒后在颗粒残余物中被蛋白酶处理，导致小鼠发生致命的过敏性休克。在 IgE-Ag介导的内毒素诱导MC脱颗粒过程中，颗粒体促进了脱颗粒，并与IL-1β的外化和加工相结合，导致严重的炎症。

附：英文原文

Title: Anaphylactic degranulation by mast cells requires the mobilization of inflammasome components

Author: Mencarelli, Andrea, Bist, Pradeep, Choi, Hae Woong, Khameneh, Hanif Javanmard, Mortellaro, Alessandra, Abraham, Soman N.

Issue&Volume: 2024-03-14

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.

DOI: 10.1038/s41590-024-01788-y

Source: https://www.nature.com/articles/s41590-024-01788-y