阻断HIF-1α/糖酵解轴通过降低ILC2代谢和功能抑制过敏性气道炎症
2024/11/29
摘要
背景：肺2组先天淋巴细胞（ILC2）活化在过敏性哮喘中的作用越来越明确。然而，ILC2介导的过敏性气道炎症中缺氧诱导因子-1α（HIF-1α）介导的糖酵解的调控机制尚不清楚。
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：采用糖酵解和HIF-1α抑制剂在体内和体外鉴定其对小鼠和人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HIF-1α缺陷小鼠来确认HIF-1α在ILC2驱动的气道炎症模型中的特定作用。进行了转录组学、代谢和染色质免疫沉淀分析，以阐明其潜在机制。
结果：HIF-1α参与ILC2代谢，在过敏性气道炎症中起着至关重要的作用。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ILC2s中糖酵解相关基因，特别是HIF-1α显著上调。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）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。转录组和代谢分析显示，与同窝对照组相比，条件性HIF-1α敲除小鼠的肺ILC2s糖酵解明显受损。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，哮喘患者HIF-1α/糖酵解轴活化受损与ILC2下调有关。
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。
Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function
Xiaogang Zhang, Jingping Liu, Xinyao Li, Guilang Zheng, Tianci Wang, Hengbiao Sun, Zhengcong Huang, Junyu He, Ju Qiu, Zhibin Zhao, Yuxiong Guo, Yumei He
Abstract
Background: The 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.
Objective: To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation.
Methods: Glycolysis 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.
Results: HIF-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.
Conclusion: The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.
背景：肺2组先天淋巴细胞（ILC2）活化在过敏性哮喘中的作用越来越明确。然而，ILC2介导的过敏性气道炎症中缺氧诱导因子-1α（HIF-1α）介导的糖酵解的调控机制尚不清楚。
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：采用糖酵解和HIF-1α抑制剂在体内和体外鉴定其对小鼠和人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HIF-1α缺陷小鼠来确认HIF-1α在ILC2驱动的气道炎症模型中的特定作用。进行了转录组学、代谢和染色质免疫沉淀分析，以阐明其潜在机制。
结果：HIF-1α参与ILC2代谢，在过敏性气道炎症中起着至关重要的作用。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ILC2s中糖酵解相关基因，特别是HIF-1α显著上调。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）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。转录组和代谢分析显示，与同窝对照组相比，条件性HIF-1α敲除小鼠的肺ILC2s糖酵解明显受损。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，哮喘患者HIF-1α/糖酵解轴活化受损与ILC2下调有关。
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。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Allergy. 2024 Oct 27. doi: 10.1111/all.16361.)
(Allergy. 2024 Oct 27. doi: 10.1111/all.16361.)
Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function
Xiaogang Zhang, Jingping Liu, Xinyao Li, Guilang Zheng, Tianci Wang, Hengbiao Sun, Zhengcong Huang, Junyu He, Ju Qiu, Zhibin Zhao, Yuxiong Guo, Yumei He
Abstract
Background: The 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.
Objective: To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation.
Methods: Glycolysis 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.
Results: HIF-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.
Conclusion: The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.
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