BackgroundThe role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia‐inducible factor‐1α (HIF‐1α)‐mediated glycolysis in ILC2‐mediated allergic airway inflammation remain unclear.ObjectiveTo investigate the role of the HIF‐1α/glycolysis axis in ILC2‐mediated allergic airway inflammation.MethodsGlycolysis and HIF‐1α inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s in vivo and vitro. Blocking glycolysis and HIF‐1α in mice under interleukin‐33 (IL‐33) stimulation were performed to test ILC2 responses. Conditional HIF‐1α‐deficient mice were used to confirm the specific role of HIF‐1α in ILC2‐driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism.ResultsHIF‐1α is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single‐cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis‐related genes, particularly HIF‐1α, in murine lung ILC2s after IL‐33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2‐deoxy‐D‐glucose (2‐DG) and the HIF‐1α inhibitor 2‐methoxyestradiol (2‐ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF‐1α‐deficient mice showed reduced ILC2 response and airway inflammation induced upon IL‐33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF‐1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis‐related genes in HIF‐1α‐knockout and 2‐DG‐treated mice. Furthermore, impaired HIF‐1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma.ConclusionThe HIF‐1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.

中文翻译：

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阻断 HIF-1α/糖酵解轴通过减少 ILC2 代谢和功能来抑制过敏性气道炎症


背景肺 2 族先天淋巴细胞 （ILC2） 激活在过敏性哮喘中的作用越来越明显。然而，在 ILC2 介导的过敏性气道炎症中，缺氧诱导因子-1α （HIF-1α） 介导的糖酵解的调节机制仍不清楚。目的探讨 HIF-1α/糖酵解轴在 ILC2 介导的过敏性气道炎症中的作用。方法糖酵解和 HIF-1α 抑制剂用于确定它们在体内和体外对小鼠和人 ILC2s 功能和葡萄糖代谢的影响。在白细胞介素-33 （IL-33） 刺激下阻断小鼠的糖酵解和 HIF-1α 以测试 ILC2 反应。使用条件性 HIF-1α 缺陷小鼠确认 HIF-1α 在 ILC2 驱动的气道炎症模型中的特定作用。进行转录组学、代谢和染色质免疫沉淀分析以阐明潜在机制。结果HIF-1α 参与 ILC2 代谢，在过敏性气道炎症中起关键作用。单细胞测序数据分析和 qPCR 确认显示，在 IL-33 鼻内给药或注射后，小鼠肺 ILC2 中糖酵解相关基因，特别是 HIF-1α 显著上调。用糖酵解抑制剂 2-脱氧-D-葡萄糖 （2-DG） 和 HIF-1α 抑制剂 2-甲氧基雌二醇 （2-ME） 治疗通过抑制 ILC2s 功能消除炎症。条件性 HIF-1α 缺陷小鼠在 IL-33 或屋尘螨 （HDM） 刺激下表现出 ILC2 反应降低和气道炎症诱导。转录组和代谢分析显示，与同窝对照组相比，条件性 HIF-1α 敲除小鼠肺 ILC2 的糖酵解显着受损。 染色质免疫沉淀结果证实了 HIF-1α 敲除和 2-DG 处理的小鼠中糖酵解相关基因的转录下调。此外，在哮喘患者中，HIF-1α/糖酵解轴激活受损与 ILC2 下调相关。结论HIF-1α/糖酵解轴对于控制过敏性气道炎症中的 ILC2 反应至关重要，在哮喘中具有潜在的免疫治疗价值。