Liu Qian, Deng Guohao, Jiang Xian, Fu Yanpeng, Zhang Jian, Wu Xue, Li Xinlong, Ai Jingang, Liu Honghui, Tan Guolin
Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China; Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China.
Department of Otolaryngology - Head and Neck Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
Int Immunopharmacol. 2025 Apr 16;152:114439. doi: 10.1016/j.intimp.2025.114439. Epub 2025 Mar 12.
Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear.
Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment.
Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased AhR nuclear translocation and higher expression of IL4I1 and the M2 macrophage marker CD206 in the lungs was observed. The IL4I1/AhR axis exacerbated allergic symptoms in AR mice, fostering allergic inflammation within the nasal mucosa and lungs.
The IL4I1/AhR axis is activated within the mononuclear phagocyte system of patients with AR. This activation facilitates the polarization of mononuclear cells into M2 macrophages, which further aggravates EMT in epithelial cells and exacerbates inflammation in AR. This study may provide novel strategies for the precise treatment of AR.
流行病学证据表明，环境污染物会促使过敏性鼻炎（AR）的发生。芳烃受体（AhR）作为多种污染物的受体或传感器，与免疫调节及M2巨噬细胞的极化密切相关。然而，AR中涉及AhR和M2巨噬细胞的机制仍不清楚。
对GEO数据集（GSE180697和GSE180697）进行生物信息学分析，评估AhR和IL4I1的表达水平，然后通过蛋白质免疫印迹法、定量实时聚合酶链反应（qRT-PCR）、免疫荧光和酶联免疫吸附测定（ELISA）在AR患者的鼻黏膜、单核细胞和血清中进行验证。使用磁分离技术从外周血中分离原代人单核细胞，并通过慢病毒构建体建立IL4I1过表达或低表达的THP-1细胞系。用细胞因子CSF、IL4和IL13诱导M2巨噬细胞，然后用AhR激动剂FICZ或抑制剂CH223191处理。通过流式细胞术和蛋白质免疫印迹法检测M2巨噬细胞的极化情况。此外，将原代鼻上皮细胞和巨噬细胞共培养，以评估上皮细胞中的上皮-间质转化（EMT）。使用卵清蛋白（OVA）建立AR小鼠模型。在给予CH223191或IL4I1处理后，检查鼻黏膜和肺组织内的炎症情况。
在AR患者的外周单核细胞和鼻黏膜组织中观察到AhR的核转位和IL4I1的上调。通过激活AhR，IL4I1促进了M2巨噬细胞的极化。此外，IL4I1/AhR轴的调节影响了OVA对T-M2细胞的迁移作用。IL4I1/AhR轴参与了M2巨噬细胞相关的EMT调节，并促进了上皮细胞中IL-33的表达和STAT6的磷酸化。在AR小鼠中，观察到肺中AhR核转位增加以及IL4I1和M2巨噬细胞标志物CD206的表达升高。IL4I1/AhR轴加剧了AR小鼠的过敏症状，促进了鼻黏膜和肺内的过敏性炎症。
AR患者的单核吞噬细胞系统中IL4I1/AhR轴被激活。这种激活促进单核细胞极化为M2巨噬细胞，进而加重上皮细胞中的EMT并加剧AR中的炎症。本研究可能为AR的精准治疗提供新策略。
