Dong Yixuan, Liu Le, Zhang Xiwen, Zheng Haoyue, Liu Yu, Zhang Aizhi, Xu Lingzhi, Zhang Yuanyi, Yang Gui, Yang Pingchang
Department of Otolaryngology. Longgang Central Hospital and Clinical College affiliated to Guangzhou University of Chinese Medicine. Shenzhen. China.
State Key Laboratory of Respiratory diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology of Shenzhen University School of Medicine, Shenzhen, China.
Immunol Lett. 2025 Oct;275:107030. doi: 10.1016/j.imlet.2025.107030. Epub 2025 Apr 30.
Th2 polarization is a central driver of allergic airway inflammation, yet the epigenetic mechanisms underlying its dysregulation remain poorly defined. Quercetin is a bioactive flavonoid with immunomodulatory properties. This study investigates whether quercetin alleviates Th2-driven pathology in allergic airway inflammation by targeting IL-10 promoter hypermethylation in airway M2 macrophages.
Using a murine model of house dust mite (Derf2)-induced allergic airway inflammation, we isolated airway M2 macrophages via flow cytometry and assessed their immunosuppressive capacity using CFSE-based T cell proliferation assays. Epigenetic regulation of Il10 was analyzed by bisulfite sequencing and chromatin immunoprecipitation. Quercetin (intranasal) was administered daily for 7 days.
Allergic mice exhibited impaired M2 cell-mediated T cell suppression (proliferation index: 85% vs. 34% in controls, P < 0.01) and IL-10 deficiency in bronchoalveolar lavage fluid (8.5 pg/ml vs. 28.2 pg/ml, P <0.001). Il10 promoter hypermethylation (72% vs. 35% methylation at CpG sites -200 to +100) and reduced KDM5A recruitment were observed in M2 cells from allergic mice. Quercetin treatment reversed these epigenetic defects, restoring KDM5A binding (P < 0.05) and Il10 transcription (2.1-fold increase, P < 0.01), thereby reducing Th2 cytokines and airway hyperresponsiveness.
Our findings identify KDM5A-mediated Il10 promoter demethylation as a critical mechanism for M2 cell immunoregulation in allergic airway inflammation. Quercetin alleviates Th2-driven pathology by restoring Il10 expression via epigenetic reprogramming of M2 macrophages. This study advances the understanding of natural compounds in targeting epigenetic checkpoints and provides a rationale for quercetin-based therapies in allergic diseases.
Th2 极化是过敏性气道炎症的核心驱动因素，但其失调背后的表观遗传机制仍不清楚。槲皮素是一种具有免疫调节特性的生物活性类黄酮。本研究调查槲皮素是否通过靶向气道 M2 巨噬细胞中白细胞介素 -10（IL-10）启动子的高甲基化来减轻过敏性气道炎症中 Th2 驱动的病理过程。
利用屋尘螨（Derf2）诱导的过敏性气道炎症小鼠模型，通过流式细胞术分离气道 M2 巨噬细胞，并使用基于羧基荧光素二乙酸琥珀酰亚胺酯（CFSE）的 T 细胞增殖试验评估其免疫抑制能力。通过亚硫酸氢盐测序和染色质免疫沉淀分析 Il10 的表观遗传调控。每天鼻内给予槲皮素，持续 7 天。
过敏性小鼠表现出 M2 细胞介导的 T 细胞抑制受损（增殖指数：对照组为 85%，过敏性小鼠为 34%，P < 0.01），支气管肺泡灌洗液中 IL-10 缺乏（8.5 皮克/毫升 vs. 28.2 皮克/毫升，P < 0.001）。在过敏性小鼠的 M2 细胞中观察到 Il10 启动子高甲基化（在 CpG 位点 -200 至 +100 处甲基化率为 72% vs. 35%）以及赖氨酸特异性去甲基化酶 5A（KDM5A）募集减少。槲皮素治疗逆转了这些表观遗传缺陷，恢复了 KDM5A 结合（P < 0.05）和 Il10 转录（增加 2.1 倍，P < 0.01），从而减少 Th2 细胞因子和气道高反应性。
我们的研究结果确定 KDM5A 介导的 Il10 启动子去甲基化是过敏性气道炎症中 M2 细胞免疫调节的关键机制。槲皮素通过对 M2 巨噬细胞进行表观遗传重编程来恢复 Il10 表达，从而减轻 Th2 驱动的病理过程。本研究推进了对天然化合物靶向表观遗传检查点的理解，并为基于槲皮素的过敏性疾病治疗提供了理论依据。
