miR-15b-5p通过HMGB1/TLR4/IL-33信号轴缓解哮喘气道重构的作用机制
2025/01/26
摘要
背景：哮喘的病理生理过程不仅以miRNA表达的显著变化为特征，还以HMGB1及其下游效应物的调控为特征。然而，miR-15b-5p和HMGB1在哮喘中的具体作用仍然知之甚少。本研究通过靶向HMGB1探讨miR-15b-5p在哮喘中的调节作用。
方法：我们使用HMGB1条件敲除小鼠(Sftpc-cre；HMGB1flox/flox)，用屋尘螨（HDM）诱导ⅱ型肺泡上皮细胞（AT2），建立小鼠哮喘模型。
结果：结果表明，AT2细胞特异性缺失HMGB1可减轻过敏原诱导的气道高反应性，减轻气道炎症。同时，野生型（WT）哮喘小鼠中miR-15b-5p水平显著降低，而HMGB1、TLR4和IL-33水平升高。给药miR-15b5p agomir反映了HMGB1敲低的作用，减少细支气管周围炎症细胞，改善气道炎症和重塑。采用荧光素酶报告基因检测系统预测并验证HMGB1是miR-15b-5p的直接靶标。过表达miR-15b-5p可显著抑制HMGB1、TLR4和IL-33的凋亡和活化，降低NLRP3、Caspase-1和IL-1 β的表达。在体外，miR-15b-5p过表达和HMGB1敲低可减弱HDM诱导的细胞炎症和裂解型caspase-9、裂解型caspase-3和Bax的产生，同时增强线粒体膜电位。
结论：本研究表明，miR-15b-5p通过抑制AT2细胞中的HMGB1/TLR4/IL-33信号通路，可作为过敏性气道炎症的保护机制。通过miR-15b-5p靶向HMGB1/TLR4/IL-33信号通路可能为哮喘提供一种潜在的治疗策略。
Mechanism of action of miR-15b-5p in alleviating asthma airway remodeling through the HMGB1/TLR4/IL-33 signaling axis
W. T. Liu, L. C. Li, Y. H. Piao, Z. G. Wang, L. Z. Dai, Y. Li, et al.
Abstract
BACKGRUND:The pathophysiologic processes of asthma are characterized not only by significant changes in miRNA expression but also by the modulation of HMGB1 and its downstream effectors. However, the specific roles of miR-15b-5p and HMGB1 in asthma remain poorly understood. This study explores the regulatory role of miR-15b-5p in asthma by targeting HMGB1.
METHODS: We utilized HMGB1-conditioned knockout mice (Sftpc-cre; HMGB1flox/flox) in type II alveolar epithelial cells (AT2), induced with house dust mite (HDM), to establish a mouse model of asthma.
RESULTS: Results demonstrated that AT2 cell-specific deletion of HMGB1 attenuated allergen-induced airway hyperresponsiveness and reduced airway inflammation. Concurrently, miR-15b-5p levels were significantly reduced in wild-type (WT) asthmatic mice, while HMGB1, TLR4, and IL-33 levels were elevated. Administration of miR-15b5p agomir mirrored the effects of HMGB1 knockdown, reducing peribronchiolar inflammatory cells and ameliorating airway inflammation and remodeling. A luciferase reporter gene assay system was employed to predict and verify HMGB1 as a direct target of miR-15b-5p. Overexpression of miR-15b-5p significantly inhibited apoptosis and activation of HMGB1, TLR4, and IL-33, and decreased NLRP3, Caspase-1, and IL-1 beta expression. In vitro, miR-15b-5p overexpression and HMGB1 knockdown attenuated HDM-induced cellular inflammation and production of Cleaved-caspase-9, Cleaved-caspase-3, and Bax, while enhancing mitochondrial membrane potential.
CONCLUSIONS: This study suggests that miR-15b-5p acts as a protective mechanism against allergic airway inflammation by inhibiting the HMGB1/TLR4/IL-33 signaling pathway in AT2 cells. Targeting the HMGB1/TLR4/IL-33 signaling by miR-15b-5p may offer a potential therapeutic strategy for asthma.
背景：哮喘的病理生理过程不仅以miRNA表达的显著变化为特征，还以HMGB1及其下游效应物的调控为特征。然而，miR-15b-5p和HMGB1在哮喘中的具体作用仍然知之甚少。本研究通过靶向HMGB1探讨miR-15b-5p在哮喘中的调节作用。
方法：我们使用HMGB1条件敲除小鼠(Sftpc-cre；HMGB1flox/flox)，用屋尘螨（HDM）诱导ⅱ型肺泡上皮细胞（AT2），建立小鼠哮喘模型。
结果：结果表明，AT2细胞特异性缺失HMGB1可减轻过敏原诱导的气道高反应性，减轻气道炎症。同时，野生型（WT）哮喘小鼠中miR-15b-5p水平显著降低，而HMGB1、TLR4和IL-33水平升高。给药miR-15b5p agomir反映了HMGB1敲低的作用，减少细支气管周围炎症细胞，改善气道炎症和重塑。采用荧光素酶报告基因检测系统预测并验证HMGB1是miR-15b-5p的直接靶标。过表达miR-15b-5p可显著抑制HMGB1、TLR4和IL-33的凋亡和活化，降低NLRP3、Caspase-1和IL-1 β的表达。在体外，miR-15b-5p过表达和HMGB1敲低可减弱HDM诱导的细胞炎症和裂解型caspase-9、裂解型caspase-3和Bax的产生，同时增强线粒体膜电位。
结论：本研究表明，miR-15b-5p通过抑制AT2细胞中的HMGB1/TLR4/IL-33信号通路，可作为过敏性气道炎症的保护机制。通过miR-15b-5p靶向HMGB1/TLR4/IL-33信号通路可能为哮喘提供一种潜在的治疗策略。
（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）
（International Immunopharmacology 2025 Vol. 145 DOI: ARTN 11375310.1016/j.intimp.2024.113753）
（International Immunopharmacology 2025 Vol. 145 DOI: ARTN 11375310.1016/j.intimp.2024.113753）
Mechanism of action of miR-15b-5p in alleviating asthma airway remodeling through the HMGB1/TLR4/IL-33 signaling axis
W. T. Liu, L. C. Li, Y. H. Piao, Z. G. Wang, L. Z. Dai, Y. Li, et al.
Abstract
BACKGRUND:The pathophysiologic processes of asthma are characterized not only by significant changes in miRNA expression but also by the modulation of HMGB1 and its downstream effectors. However, the specific roles of miR-15b-5p and HMGB1 in asthma remain poorly understood. This study explores the regulatory role of miR-15b-5p in asthma by targeting HMGB1.
METHODS: We utilized HMGB1-conditioned knockout mice (Sftpc-cre; HMGB1flox/flox) in type II alveolar epithelial cells (AT2), induced with house dust mite (HDM), to establish a mouse model of asthma.
RESULTS: Results demonstrated that AT2 cell-specific deletion of HMGB1 attenuated allergen-induced airway hyperresponsiveness and reduced airway inflammation. Concurrently, miR-15b-5p levels were significantly reduced in wild-type (WT) asthmatic mice, while HMGB1, TLR4, and IL-33 levels were elevated. Administration of miR-15b5p agomir mirrored the effects of HMGB1 knockdown, reducing peribronchiolar inflammatory cells and ameliorating airway inflammation and remodeling. A luciferase reporter gene assay system was employed to predict and verify HMGB1 as a direct target of miR-15b-5p. Overexpression of miR-15b-5p significantly inhibited apoptosis and activation of HMGB1, TLR4, and IL-33, and decreased NLRP3, Caspase-1, and IL-1 beta expression. In vitro, miR-15b-5p overexpression and HMGB1 knockdown attenuated HDM-induced cellular inflammation and production of Cleaved-caspase-9, Cleaved-caspase-3, and Bax, while enhancing mitochondrial membrane potential.
CONCLUSIONS: This study suggests that miR-15b-5p acts as a protective mechanism against allergic airway inflammation by inhibiting the HMGB1/TLR4/IL-33 signaling pathway in AT2 cells. Targeting the HMGB1/TLR4/IL-33 signaling by miR-15b-5p may offer a potential therapeutic strategy for asthma.
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缺氧诱导因子2α通过调节磷脂代谢促进干细胞样Th2细胞的致病极化
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BRCC3的缺失通过抑制NLRP3炎性体的激活来改善哮喘患者的气道炎症
