Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation

作者全名："Wu, Siqi; Tang, Wenjing; Liu, Ling; Wei, Ke; Tang, Yin; Ma, Jingyue; Li, Hongbin; Ao, Yichan"

作者地址："[Wu, Siqi; Tang, Wenjing; Liu, Ling; Wei, Ke; Tang, Yin; Ma, Jingyue; Li, Hongbin; Ao, Yichan] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 1, 1 YouYi Rd, Chongqing 400016, Peoples R China"

通信作者："Liu, L; Wei, K (通讯作者)，Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 1, 1 YouYi Rd, Chongqing 400016, Peoples R China."

来源：CELLULAR & MOLECULAR BIOLOGY LETTERS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001185283500001

JCR分区：Q1

影响因子：9.2

年份：2024

卷号：29

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Obesity; Acute lung injury; microRNA; Macrophage activation; m6A; Metabolic stress

摘要："BackgroundMacrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity.MethodsHuman lung tissues were obtained from obese patients (BMI >= 30.0 kg/m2) and control patients (BMI 18.5-24.9 kg/m2). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192.ResultsIn obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-kappa B inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge.ConclusionsOur study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI."

基金机构：Chongqing Science & Technology Bureau; First Affiliated Hospital of Chongqing Medical University

基金资助正文："We would like to thank the experimental conditions provided by the Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University."