Gao Yajing, Liu Kwei-Yan, Xiao Wenfeng, Xie Xueru, Liang Qiuyan, Tu Zikun, Yang Lan, Yu Hongmiao, Guo Haiyan, Huang Saihua, Han Xiao, Fu Jinrong, Zhou Yufeng
Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
Theranostics. 2024 Jul 8;14(11):4218-4239. doi: 10.7150/thno.95749. eCollection 2024.
The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. The cellular composition of intestinal lamina propria CD45 leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45 immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 () transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K efflux. expression was positively correlated with in intestinal mucosal biopsies from patients with ulcerative colitis. These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.
芳香烃受体（AhR）在肠道炎症调节中发挥作用，但对先天免疫细胞中潜在机制的了解有限。在此，我们研究了AhR在炎症性肠病发病机制中调节巨噬细胞功能的作用。通过单细胞RNA测序确定葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中肠道固有层CD45白细胞的细胞组成。通过分析乳酸脱氢酶释放、碘化丙啶染色、酶联免疫吸附测定、蛋白质免疫印迹和流式细胞术对巨噬细胞焦亡进行定量。通过RNA测序、逆转录定量聚合酶链反应、荧光素酶测定、染色质免疫沉淀和免疫荧光染色对差异表达基因进行确认。AhR缺陷介导了结肠炎模型中肠道固有层（LP）CD45免疫细胞细胞组成的动态重塑，单核细胞-巨噬细胞谱系显著增加。髓系细胞中缺乏AhR的小鼠发生更严重的葡聚糖硫酸钠诱导的结肠炎，同时巨噬细胞焦亡增加。用AhR前配体吲哚-3-甲醇进行饮食补充可预防结肠炎，而在髓系细胞中缺乏AhR的小鼠中则无法起到保护作用。机制上，AhR信号通过促进鸟氨酸脱羧酶1（ODC1）转录来抑制巨噬细胞焦亡，以增强多胺生物合成。增加的多胺，特别是精胺，通过抑制钾外流来抑制NLRP3炎性小体组装及随后的焦亡。在溃疡性结肠炎患者的肠道黏膜活检中，ODC1表达与AhR呈正相关。这些发现表明AhR/ODC1/多胺轴在维持肠道稳态中具有功能作用，为炎症性肠病的治疗提供了潜在靶点。
