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溶解体通过TRPML1通道调节溶解体Fe2+的释放,精细控制巨细胞的炎症功能

Yanhong Xing¹, Meng-Meng Wang², Feifei Zhang¹

¹Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Nature communications

|January 24, 2025

概括

溶解体通过TRPML1通道调节巨细胞炎症,该通道抑制了互白素-1β (IL1B) 转录. 这一途径为炎症性肠病提供了潜在的治疗策略.

科学领域:

细胞生物学细胞生物学
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

溶解体在炎症反应中至关重要,主要是通过自来清除炎症体.
阐明了一种控制巨细胞炎症功能的新型 lysosomal 途径.
这一途径涉及溶酶体铁 (Fe2+) 依赖的prolyl氧化酶域酶 (PHDs) -NF-κB-介质素1β (IL1B) 转录.

研究的目的:

揭示 lysosomes 在调节巨细胞炎症功能的之前未知的作用.
调查溶酶体TRPML1通道影响炎症基因转录的机制.
评估TRPML1调制在炎症条件下的治疗潜力.

主要方法:

研究了 lysosomal 阴阳性通道 TRPML1 对炎症刺激的反应中的作用.
研究了TRPML1激活对巨细胞中互白素1β (IL1B) 转录的影响.
分析了涉及 lysosomal Fe2+ 释放,prolyl hydroxylase 域酶 (PHD) 激活和NF-κB 信号传递的机制.
在小鼠模型中评估了TRPML1刺激的体内疗效,Dextran硫酸盐诱导大肠炎.

主要成果:

在炎症期间由活性氧物种 (ROS) 触发的TRPML1激活抑制IL1B转录.
TRPML1调节溶酶体Fe2+释放,导致PHD激活.
激活的PHD抑制NF-κB的转录活性,从而减少IL1B的表达.
活体TRPML1刺激显著改善了小鼠大肠炎的临床症状.

结论:

溶解体在通过TRPML1-PHD-NF-κB-IL1B通路微调巨细胞炎症反应中发挥着至关重要的作用.
TRPML1的激活作为一个负反机制,以限制过度的IL-1β生产.
准TRPML1显示了炎症性肠病的治疗潜力.

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