注射用两性霉素 B 通过 MRGPRX2 触发人 LAD2 肥大细胞脱颗粒,并通过 MRGPRB2 激活小鼠的假过敏反应。

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Immunologic Research Pub Date : 2024-12-01 Epub Date: 2024-09-03 DOI:10.1007/s12026-024-09532-2
Xu He, Xinxin Yang, Longyu Qin, Qianqian Zhang, Xiaolan Ji, Wenjuan Tang, Yingzhuan Zhan, Yanmin Zhang
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引用次数: 0

摘要

两性霉素 B 是一种多烯大环内酯类抗真菌药物,在治疗严重的全身性真菌感染方面仍然发挥着重要作用。脱氧胆酸两性霉素 B(AmBd)用于治疗侵袭性真菌感染已有 60 多年的历史,目前仍是主要的临床制剂。在临床上,AmBd 引发的过敏性反应已有文献记载。然而,迄今为止,导致这些反应的分子和细胞事件尚未得到明确阐明。本研究证明,人类 Mas 相关 G 蛋白偶联受体 X2(MRGPRX2)是介导这些过敏反应的受体。分子对接和细胞热转移测定(CETSA)表明,AmBd 与 MRGPRX2 具有潜在的亲和力。在体外,暴露于 AmBd 会导致 LAD2 肥大细胞颗粒的显著释放,并诱导细胞内 Ca2+ 的动员以及 PLC-γ/IP3R 和 PI3K/AKT 信号通路的激活。然而,在 MRGPRX2 敲除的 LAD2 细胞中,这些现象都有所减少。在体内,AmBd 会引发野生型(WT)小鼠爪肿胀和核心体温迅速下降。然而,这些反应在 MRGPRB2(MRGPRX2 的小鼠同源物)基因敲除小鼠(MRGPRB2MUT,MUT)中几乎不存在。上述结果表明,AmBd 通过 MRGPRX2(在人类 LAD2 肥大细胞中)或 MRGPRB2(在小鼠中)激活 PLC-γ/IP3R 和 PI3K/AKT 信号,导致肥大细胞颗粒释放,进而引发假性过敏反应。综上所述,本研究阐明了 MRGPRX2 在引发对 AmBd 的假性过敏反应中的作用,并表明 MRGPRX2 可能是控制这些反应的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Amphotericin B for injection triggers degranulation of human LAD2 mast cells by MRGPRX2 and pseudo-allergic reactions in mice via MRGPRB2 activation.

Amphotericin B for injection triggers degranulation of human LAD2 mast cells by MRGPRX2 and pseudo-allergic reactions in mice via MRGPRB2 activation.

Amphotericin B, a polyene macrolide antifungal agent, still plays an important role in the management of serious systemic fungal infections. Amphotericin B deoxycholate (AmBd) has been used to treat invasive fungal infections for over 60 years and remains the primary clinical formulation currently available. Anaphylactoid reactions triggered by AmBd in the clinic have been documented. However, the molecular and cellular events contributing to these reactions have not been clearly elucidated to date. This study demonstrates that the human Mas-related G protein-coupled receptor X2 (MRGPRX2) is the receptor that mediates these anaphylactoid responses. Molecular docking and cellular thermal shift assay (CETSA) indicate that AmBd exhibits potential affinity with MRGPRX2. In vitro, exposure to AmBd results in significant release of LAD2 mast cell granules and induces intracellular Ca2+ mobilization as well as activation of PLC-γ/IP3R and PI3K/AKT signaling pathways. However, these phenomena are reduced in MRGPRX2-knockdown LAD2 cells. In vivo, AmBd triggers paw swelling and a rapid drop in core body temperature in wild-type (WT) mice. However, these reactions are almost absent in MRGPRB2 (the mouse homolog of MRGPRX2) knockout mice (MRGPRB2MUT, MUT). The above results suggest that AmBd activates PLC-γ/IP3R and PI3K/AKT signaling via MRGPRX2 (in human LAD2 mast cells) or MRGPRB2 (in mice), leading to the release of mast cell granules and subsequent triggering of pseudo-allergic reactions. Taken together, this study clarifies the role of MRGPRX2 in triggering pseudo-allergic reactions to AmBd and suggests that MRGPRX2 could be a potential therapeutic target for controlling these reactions.

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来源期刊
Immunologic Research
Immunologic Research 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
83
审稿时长
6-12 weeks
期刊介绍: IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.
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