Wu Huanwen, Zhao Qijiang, Dong Liangliang, Wu Yuxin, Zheng Chengzhi, Wu Tongquan, Ma Daqing, Xie Yicheng, Wang Yingshuo
Perioperative and Systems Medicine Laboratory, Department of Pulmonology, Laboratory Animal Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
Zhejiang Key Laboratory of Neonatal Diseases, Hangzhou, 310052, China.
Inflamm Res. 2025 Aug 25;74(1):113. doi: 10.1007/s00011-025-02082-9.
Pulmonary inflammation is closely associated with macrophage polarization and lipid metabolic reprogramming. Miconazole (MCZ), traditionally used as an antifungal agent, exhibits emerging anti-inflammatory potential, yet its underlying mechanisms remain unclear.
A mouse model of lipopolysaccharide (LPS)-induced lung inflammation was employed to evaluate MCZ's anti-inflammatory efficacy. In vivo inflammatory cell infiltration, cytokine expression (IL-6, IL-1β, TNF-α), and lung histopathology were assessed. Single-cell RNA sequencing (scRNA-seq) characterized alveolar macrophage subpopulations and associated lipid metabolism pathways. In vitro experiments with bone marrow-derived macrophages (BMDM) validated the changes of macrophage polarization.
MCZ treatment significantly alleviated lung inflammation by decreasing inflammatory cell infiltration and suppressing pro-inflammatory cytokines. ScRNA-seq analysis revealed subcluster of Itgam (Cd11b) negative, Mrc1, Marco, and Lgals3 high AMs, MCZ decreased the proportions of pro-inflammatory neutrophils and macrophages, and promoted the phenotypic shift of alveolar macrophages from a pro-inflammatory subtype (AM1) to an anti-inflammatory subtype (AM2). Further cell-cell communication analysis showed that MCZ suppressed interactions between AM1 alveolar macrophages and neutrophils via TNF-TNFR, CCL3/5-CCR1, and CXCL1-CXCR2 signaling pathways. Mechanistically, MCZ inhibited lipid synthesis in AM1 alveolar macrophages while enhancing lipid catabolism in AM2 alveolar macrophages. In vitro studies using BMDM further confirmed that MCZ inhibited LPS-induced macrophage M1 polarization and lipid droplet accumulation marked by perilipin 3 (PLIN3), while promoting IL-4/IL-13-induced M2 polarization.
MCZ exerts therapeutic effects against pulmonary inflammation primarily by modulating macrophage polarization through lipid metabolic reprogramming, highlighting its promise as a novel therapeutic approach for inflammatory lung diseases.
肺部炎症与巨噬细胞极化和脂质代谢重编程密切相关。咪康唑（MCZ）传统上用作抗真菌剂，具有新出现的抗炎潜力，但其潜在机制尚不清楚。
采用脂多糖（LPS）诱导的小鼠肺部炎症模型评估MCZ的抗炎效果。评估体内炎症细胞浸润、细胞因子表达（IL-6、IL-1β、TNF-α）和肺组织病理学。单细胞RNA测序（scRNA-seq）对肺泡巨噬细胞亚群和相关脂质代谢途径进行了表征。用骨髓来源的巨噬细胞（BMDM）进行的体外实验验证了巨噬细胞极化的变化。
MCZ治疗通过减少炎症细胞浸润和抑制促炎细胞因子，显著减轻了肺部炎症。ScRNA-seq分析揭示了Itgam（Cd11b）阴性、Mrc1、Marco和Lgals3高表达的AMs亚群，MCZ降低了促炎中性粒细胞和巨噬细胞的比例，并促进肺泡巨噬细胞从促炎亚型（AM1）向抗炎亚型（AM2）的表型转变。进一步的细胞间通讯分析表明，MCZ通过TNF-TNFR、CCL3/5-CCR1和CXCL1-CXCR2信号通路抑制AM1肺泡巨噬细胞与中性粒细胞之间的相互作用。机制上，MCZ抑制AM1肺泡巨噬细胞中的脂质合成，同时增强AM2肺泡巨噬细胞中的脂质分解代谢。使用BMDM的体外研究进一步证实，MCZ抑制LPS诱导的巨噬细胞M1极化和以 perilipin 3（PLIN3）为标记的脂滴积累，同时促进IL-4/IL-13诱导的M2极化。
MCZ主要通过脂质代谢重编程调节巨噬细胞极化，对肺部炎症发挥治疗作用，突出了其作为炎症性肺病新型治疗方法的前景。
