Liu Wanting, Li Liangchang, Piao Yihua, Wang Zhiguang, Dai Longzhu, Li Yan, Piao Hongmei, Song Yilan, Cui Qingsong, Wang Chongyang, Yan Guanghai
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China; Heilongjiang provincial Clinical Medical Research Center for Chemical Poisoning, The Second Hospital of Heilongjiang Province, Harbin 150028, PR China.
Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China.
Int Immunopharmacol. 2025 Jan 3;145:113753. doi: 10.1016/j.intimp.2024.113753. Epub 2024 Dec 6.
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. We utilized HMGB1-conditioned knockout mice (Sftpc-cre; HMGB1) in type II alveolar epithelial cells (AT2), induced with house dust mite (HDM), to establish a mouse model of asthma. 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-15b-5p 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-1β 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. 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.
哮喘的病理生理过程不仅以微小RNA（miRNA）表达的显著变化为特征，还以高迁移率族蛋白B1（HMGB1）及其下游效应分子的调节为特征。然而，miR-15b-5p和HMGB1在哮喘中的具体作用仍知之甚少。本研究通过靶向HMGB1探讨miR-15b-5p在哮喘中的调节作用。我们利用II型肺泡上皮细胞（AT2）中HMGB1条件性敲除小鼠（Sftpc-cre；HMGB1），用屋尘螨（HDM）诱导，建立哮喘小鼠模型。结果表明，AT2细胞特异性敲除HMGB1可减轻变应原诱导的气道高反应性并减轻气道炎症。同时，野生型（WT）哮喘小鼠中miR-15b-5p水平显著降低，而HMGB1、Toll样受体4（TLR4）和白细胞介素33（IL-33）水平升高。给予miR-15b-5p激动剂可模拟HMGB1敲低的效果，减少细支气管周围炎性细胞，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的直接靶点。miR-15b-5p的过表达显著抑制HMGB1、TLR4和IL-33的凋亡和激活，并降低NLR家族含pyrin结构域蛋白3（NLRP3）、半胱天冬酶-1（Caspase-1）和IL-1β的表达。在体外，miR-15b-5p过表达和HMGB1敲低可减轻HDM诱导的细胞炎症以及裂解的半胱天冬酶-9（Cleaved-caspase-9）、裂解的半胱天冬酶-3（Cleaved-caspase-3）和Bax的产生，同时增强线粒体膜电位。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，作为一种针对过敏性气道炎症的保护机制。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。
