Zhao Miao, Zhang Hanqing, Liu Zhiqiang, Liu Jiangqi, Xie Bailing, Zeng Lu, Wang Xiangyu, Shu Qing, Tang Ping, Mo Lihua, Zeng Haotao, Yang Pingchang
Department of Otolaryngology, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China.
State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
Immunol Lett. 2025 Dec;276:107035. doi: 10.1016/j.imlet.2025.107035. Epub 2025 May 20.
Mast cells play pivotal roles in allergic pathogenesis and inflammatory disorders, with their pathologic effects largely mediated through granule exocytosis. Dynactin subunit 1 (Dctn1), a microtubule-associated motor protein, remains unexplored in mast cell-driven inflammation. This study investigates Dctn1's functional role in regulating mast cell degranulation during food allergy (FA).
An ovalbumin-sensitized murine FA model was established to profile mast cell activity. Gut lavage fluid (GLF) was analyzed via Olink proteomics and ELISA to quantify Dctn1 levels and mast cell mediators (histamine, Mcpt1). Mechanistic studies employed RNA interference, conditional knockout mice (Dctn1Cma1-Cre), and immunoprecipitation to assess Dctn1's role in granule trafficking.
FA mice exhibited 3.2-fold higher Dctn1 levels in GLF versus controls (p < 0.001), strongly correlating with mast cell mediator concentrations (histamine: r = 0.73; Mcpt1: r = 0.7). Intestinal mast cells showed selective Dctn1 upregulation (2.8-fold mRNA increase, p < 0.01), mechanistically linked to granule trafficking through CMA1 complex formation. Mast cell-specific Dctn1 ablation reduced Mcpt1 release by 74 % (p < 0.001) and ameliorated FA symptoms (92 % core temperature drop, p < 0.005), independent of AKT/ERK signaling pathways.
This study identifies Dctn1 as a novel regulator of mast cell degranulation in FA, operating through microtubule-dependent granule transport. Targeted inhibition of Dctn1 significantly attenuates allergic responses without disrupting canonical activation signals, positioning it as a promising therapeutic target for mast cell-driven pathologies.
肥大细胞在过敏性发病机制和炎症性疾病中起关键作用，其病理效应主要通过颗粒胞吐作用介导。动力蛋白激活蛋白亚基1（Dctn1）是一种与微管相关的运动蛋白，在肥大细胞驱动的炎症中尚未得到研究。本研究调查了Dctn1在食物过敏（FA）期间调节肥大细胞脱颗粒中的功能作用。
建立卵清蛋白致敏的小鼠FA模型以分析肥大细胞活性。通过Olink蛋白质组学和酶联免疫吸附测定法分析肠道灌洗液（GLF），以量化Dctn1水平和肥大细胞介质（组胺、Mcpt1）。机制研究采用RNA干扰、条件性敲除小鼠（Dctn1Cma1-Cre）和免疫沉淀来评估Dctn1在颗粒运输中的作用。
与对照组相比，FA小鼠GLF中的Dctn1水平高3.2倍（p<0.001），与肥大细胞介质浓度密切相关（组胺：r=0.73；Mcpt1：r=0.7）。肠道肥大细胞显示Dctn1选择性上调（mRNA增加2.8倍，p<0.01），其机制与通过CMA1复合物形成的颗粒运输有关。肥大细胞特异性Dctn1缺失使Mcpt1释放减少74%（p<0.001），并改善了FA症状（核心体温下降92%，p<0.005），这与AKT/ERK信号通路无关。
本研究确定Dctn1是FA中肥大细胞脱颗粒的新型调节因子，通过微管依赖性颗粒运输发挥作用。靶向抑制Dctn1可显著减轻过敏反应，而不会破坏经典激活信号，使其成为肥大细胞驱动疾病的有前景的治疗靶点。
