2. Academic Validation
  3. Mechanism of action of miR-15b-5p in alleviating asthma airway remodeling through the HMGB1/TLR4/IL-33 signaling axis

Mechanism of action of miR-15b-5p in alleviating asthma airway remodeling through the HMGB1/TLR4/IL-33 signaling axis

  • Int Immunopharmacol. 2025 Jan 3:145:113753. doi: 10.1016/j.intimp.2024.113753.
Wanting Liu 1,  Liangchang Li 2,  Yihua Piao 3,  Zhiguang Wang 4,  Longzhu Dai 2,  Yan Li 4,  Hongmei Piao 3,  Yilan Song 2,  Qingsong Cui 4,  Chongyang Wang 5,  Guanghai Yan 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Critical Care Medicine, Affiliated Hospital of Yanbian University, Yanji 133000, PR China.
  • 4 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Respiratory Medicine, Affiliated Hospital of Yanbian University, Yanji 133000, PR China.
  • 5 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. Electronic address: m18804331583@163.com.
  • 6 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. Electronic address: ghyan2015@sina.com.
PMID: 39644790 DOI: 10.1016/j.intimp.2024.113753
Abstract

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; HMGB1flox/flox) 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.

Keywords

Asthma; HMGB1; IL-33; TLR4; miR-15b-5p.

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