KLF5介导的气道上皮细胞凋亡通过 miR-182-5p/TLR4轴导致哮喘小鼠的气道炎症
2024/04/24
摘要
背景：哮喘被认为是一种气道疾病和炎症。本研究旨在揭示 Kruppel 样因子 5（KLF5）介导的气道上皮细胞凋亡在哮喘气道炎症中的作用。
方法：建立哮喘小鼠模型。用含有sh-KLF5、antagomiR-182-5p和pc-Toll-like receptor 4 (TLR4)的慢病毒感染小鼠。测量气道高反应性，并对支气管肺泡灌洗液（BALF）中的细胞进行分类和计数。检测IL-4/IL-13/IL-6/IL-18/IL-1β/类NOD受体家族含吡咯啉结构域3（NLRP3）/N-气蛋白D（GSDMD-N）/caspase-1的表达水平。观察肺组织的病理变化。测定KLF5在miR-182-5p启动子区域的富集程度。分析KLF5、miR-182-5p和TLR4之间的结合关系。
结果：KLF5在哮喘小鼠中高表达。沉默KLF5可改善气道阻力和肺动态顺应性，减少BALF中细胞及IL-4/IL-13/IL-6/NLRP3/GSDMD-N/cleaved caspase-1/IL-18/IL-1β的表达，减轻病理改变。从机制上看，KLF5与miR-182-5p启动子结合抑制了miR-182-5p的表达，而miR-182-5p抑制了TLR4。沉默 miR-182-5p 或过表达 TLR4 可逆转沉默 KLF5 对哮喘小鼠气道炎症和焦亡的改善作用。
结论：总之，KLF5能抑制miR-182-5p，促进TLR4的表达，从而加重哮喘小鼠的焦亡和气道炎症。
KLF5-mediated pyroptosis of airway epithelial cells leads to airway inflammation in asthmatic mice through the miR-182-5p/TLR4 axis
Z. Lin, R. Bao, Y. Niu and X. Kong
Abstract
BACKGROUND:Asthma is viewed as an airway disease and an inflammatory condition. This study aims to reveal the role of Kruppel-like factor 5 (KLF5)-mediated pyroptosis of airway epithelial cells in airway inflammation in asthma.
METHODS:The asthmatic mouse model was established. The mice were infected with the lentivirus containing sh-KLF5, antagomiR-182-5p, and pc-Toll-like receptor 4 (TLR4). Airway hyperresponsiveness was measured, and the cells in bronchoalveolar lavage fluid (BALF) were sorted and counted. The expression levels of interleukin (IL)-4/IL-13/IL-6/IL-18/IL-1beta/NOD-like receptor family pyrin domain containing 3 (NLRP3)/N-gasdermin D (GSDMD-N)/cleaved caspase-1 were detected. The pathological changes in lung tissue were observed. The enrichment of KLF5 in the miR-182-5p promoter region was measured. The binding relationship among KLF5, miR-182-5p, and TLR4 were analyzed.
RESULTS:KLF5 was highly expressed in asthmatic mice. Silencing KLF5 improved airway resistance and lung dynamic compliance, reduced the cells in BALF and the expression of IL-4/IL-13/IL-6/NLRP3/GSDMD-N/cleaved caspase-1/IL-18/IL-1beta, and alleviated the pathological changes. Mechanistically, KLF5 bonded to the miR-182-5p promoter to inhibit miR-182-5p expression, and miR-182-5p inhibited TLR4. Silencing miR-182-5p or TLR4 overexpression reversed the improvement of silencing KLF5 on airway inflammation and pyroptosis in asthmatic mice.
CONCLUSION:In conclusion, KLF5 inhibited miR-182-5p to promote TLR4 expression, thus aggravating pyroptosis and airway inflammation in asthmatic mice.
背景：哮喘被认为是一种气道疾病和炎症。本研究旨在揭示 Kruppel 样因子 5（KLF5）介导的气道上皮细胞凋亡在哮喘气道炎症中的作用。
方法：建立哮喘小鼠模型。用含有sh-KLF5、antagomiR-182-5p和pc-Toll-like receptor 4 (TLR4)的慢病毒感染小鼠。测量气道高反应性，并对支气管肺泡灌洗液（BALF）中的细胞进行分类和计数。检测IL-4/IL-13/IL-6/IL-18/IL-1β/类NOD受体家族含吡咯啉结构域3（NLRP3）/N-气蛋白D（GSDMD-N）/caspase-1的表达水平。观察肺组织的病理变化。测定KLF5在miR-182-5p启动子区域的富集程度。分析KLF5、miR-182-5p和TLR4之间的结合关系。
结果：KLF5在哮喘小鼠中高表达。沉默KLF5可改善气道阻力和肺动态顺应性，减少BALF中细胞及IL-4/IL-13/IL-6/NLRP3/GSDMD-N/cleaved caspase-1/IL-18/IL-1β的表达，减轻病理改变。从机制上看，KLF5与miR-182-5p启动子结合抑制了miR-182-5p的表达，而miR-182-5p抑制了TLR4。沉默 miR-182-5p 或过表达 TLR4 可逆转沉默 KLF5 对哮喘小鼠气道炎症和焦亡的改善作用。
结论：总之，KLF5能抑制miR-182-5p，促进TLR4的表达，从而加重哮喘小鼠的焦亡和气道炎症。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Molecular immunology 2024 Vol. 170 Pages 9-18 DOI: 10.1016/j.molimm.2024.03.007）
（Molecular immunology 2024 Vol. 170 Pages 9-18 DOI: 10.1016/j.molimm.2024.03.007）
KLF5-mediated pyroptosis of airway epithelial cells leads to airway inflammation in asthmatic mice through the miR-182-5p/TLR4 axis
Z. Lin, R. Bao, Y. Niu and X. Kong
Abstract
BACKGROUND:Asthma is viewed as an airway disease and an inflammatory condition. This study aims to reveal the role of Kruppel-like factor 5 (KLF5)-mediated pyroptosis of airway epithelial cells in airway inflammation in asthma.
METHODS:The asthmatic mouse model was established. The mice were infected with the lentivirus containing sh-KLF5, antagomiR-182-5p, and pc-Toll-like receptor 4 (TLR4). Airway hyperresponsiveness was measured, and the cells in bronchoalveolar lavage fluid (BALF) were sorted and counted. The expression levels of interleukin (IL)-4/IL-13/IL-6/IL-18/IL-1beta/NOD-like receptor family pyrin domain containing 3 (NLRP3)/N-gasdermin D (GSDMD-N)/cleaved caspase-1 were detected. The pathological changes in lung tissue were observed. The enrichment of KLF5 in the miR-182-5p promoter region was measured. The binding relationship among KLF5, miR-182-5p, and TLR4 were analyzed.
RESULTS:KLF5 was highly expressed in asthmatic mice. Silencing KLF5 improved airway resistance and lung dynamic compliance, reduced the cells in BALF and the expression of IL-4/IL-13/IL-6/NLRP3/GSDMD-N/cleaved caspase-1/IL-18/IL-1beta, and alleviated the pathological changes. Mechanistically, KLF5 bonded to the miR-182-5p promoter to inhibit miR-182-5p expression, and miR-182-5p inhibited TLR4. Silencing miR-182-5p or TLR4 overexpression reversed the improvement of silencing KLF5 on airway inflammation and pyroptosis in asthmatic mice.
CONCLUSION:In conclusion, KLF5 inhibited miR-182-5p to promote TLR4 expression, thus aggravating pyroptosis and airway inflammation in asthmatic mice.
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血清细胞外囊泡中的 Galectin-10 反映了哮喘的病理生理学特征
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哮喘及上皮的气道重塑:在一个新时代的边缘
