Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, China.
Int Immunopharmacol. 2024 Apr 20;131:111917. doi: 10.1016/j.intimp.2024.111917. Epub 2024 Mar 24.
Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.
热休克蛋白 90α（HSP90α）是伴侣蛋白 HSP90 的主要亚型，涉及 DNA 损伤修复、蛋白质修饰、固有免疫等重要的生物学功能。然而，HSP90α 在哮喘发生和发展中的潜在作用尚不清楚。本研究旨在通过关注炎症性气道上皮细胞死亡（即细胞焦亡；炎症细胞死亡）中的 cGAS-STING-内质网应激途径，阐明 HSP90α 在哮喘中的作用机制。为此，我们使用屋尘螨模拟变应原暴露在 C57/6BL 小鼠和支气管上皮细胞中。利用蛋白质技术和免疫荧光技术研究 HSP90α 的表达、cGAS-STING 途径的激活和细胞焦亡。通过组织学技术和支气管肺泡灌洗液检查检测 HSP90 抑制剂对 HDM 暴露小鼠的影响。结果表明，HSP90α 通过细胞焦亡和 cGAS-STING-内质网应激途径的激活促进哮喘炎症。HSP90 抑制剂坦那西普（17-AAG）治疗显著缓解气道炎症，并在体外和体内 HDM 模型中消除 HSP90α 对细胞焦亡和 cGAS-STING-内质网应激的作用。进一步的数据表明，HSP90α 的上调通过相互作用稳定了 STING，从而增加了 STING 在 ER 上的定位。STING 的激活触发了内质网应激，并导致与细胞焦亡相关的气道炎症。该发现表明 HSP90α 对气道上皮细胞的失调导致细胞焦亡在过敏性炎症中的潜在作用，提示靶向气道上皮细胞中的 HSP90α 可能成为哮喘的一种潜在治疗策略。
