Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
Exp Lung Res. 2023;49(1):49-62. doi: 10.1080/01902148.2023.2170494. Epub 2023 Jan 31.
Endoplasmic reticulum (ER) stress regulates mucus hypersecretion, and may activate downstream factors via TBK1 signaling to induce gene expression. However, it remains unclear whether ER stress promotes airway mucus secretion through the TBK1 pathway. We aimed to investigate the role of the TBK1 pathway in the regulation of MUC5AC expression in a mouse model of house dust mite (HDM)-induced allergic asthma. Mice with HDM-induced asthma and human bronchial epithelial BEAS-2B cells were treated with amlexanox, an anti-allergy drug (25 μM), or 4-PBA (10 mM). Tissue and cell samples were collected. Tissue samples were stained with hematoxylin and eosin (H&E) or periodic acid Schiff (PAS) to evaluate pathology. Protein expression was analyzed by western blotting and immunofluorescence. Mice exposed to HDM presented ER stress and hypersecretion of mucus Muc5ac from airway epithelial cells ( < 0.001). Similar results were observed in BEAS-2B cells following exposure to HDM. Both and studies revealed that HDM-induced ER stress induced MUC5AC overexpression via TBK1 signaling. Amlexanox and 4-PBA markedly reduced mucus production and weakened the TBK1 signal, which mediates MUC5AC hypersecretion. TBK1 plays a pivotal role in HDM-induced ER stress, leading to overproduction of MUC5AC in the asthmatic airway epithelium. The overproduction of MUC5AC can be significantly decreased by inhibiting TBK1 or ER stress using 4-PBA. These findings highlight potential target-specific therapies for patients with chronic allergic asthma.
内质网（ER）应激调节黏液高分泌，并可能通过 TBK1 信号转导激活下游因子，诱导基因表达。然而，内质网应激是否通过 TBK1 途径促进气道黏液分泌仍不清楚。我们旨在研究 TBK1 途径在屋尘螨（HDM）诱导的过敏性哮喘小鼠模型中调节 MUC5AC 表达中的作用。用抗变态反应药物（25 μM）氨来占诺或 4-PBA（10 mM）处理 HDM 诱导哮喘的小鼠和人支气管上皮 BEAS-2B 细胞。收集组织和细胞样本。用苏木精和伊红（H&E）或过碘酸希夫（PAS）染色评估组织病理学。通过 Western blot 和免疫荧光分析蛋白表达。暴露于 HDM 的小鼠表现出内质网应激和气道上皮细胞中黏液 Muc5ac 的过度分泌（<0.001）。BEAS-2B 细胞暴露于 HDM 后也观察到类似的结果。两项研究均表明，HDM 诱导的内质网应激通过 TBK1 信号诱导 MUC5AC 过度表达。氨来占诺和 4-PBA 显著减少黏液产生并减弱介导 MUC5AC 过度分泌的 TBK1 信号。TBK1 在 HDM 诱导的内质网应激中起关键作用，导致哮喘气道上皮中 MUC5AC 的过度产生。用 4-PBA 抑制 TBK1 或内质网应激可显著减少 MUC5AC 的过度产生。这些发现为慢性过敏性哮喘患者提供了潜在的靶向特异性治疗方法。
