Zhang Xiaogang, Liu Jingping, Li Xinyao, Zheng Guilang, Wang Tianci, Sun Hengbiao, Huang Zhengcong, He Junyu, Qiu Ju, Zhao Zhibin, Guo Yuxiong, He Yumei
Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
Department of Clinical Laboratory, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
Allergy. 2025 May;80(5):1309-1334. doi: 10.1111/all.16361. Epub 2024 Oct 27.
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.
To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation.
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.
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.
The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.
肺部2型天然淋巴细胞（ILC2）激活在过敏性哮喘中的作用日益明确。然而，在ILC2介导的过敏性气道炎症中，缺氧诱导因子-1α（HIF-1α）介导的糖酵解的调控机制仍不清楚。
研究HIF-1α/糖酵解轴在ILC2介导的过敏性气道炎症中的作用。
使用糖酵解抑制剂和HIF-1α抑制剂，在体内和体外确定它们对小鼠和人类ILC2功能及葡萄糖代谢的影响。在白细胞介素-33（IL-33）刺激下，对小鼠进行糖酵解和HIF-1α阻断，以测试ILC2反应。使用条件性HIF-1α缺陷小鼠，在ILC2驱动的气道炎症模型中确认HIF-1α的特定作用。进行转录组、代谢和染色质免疫沉淀分析，以阐明潜在机制。
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证实，经鼻内给予或注射IL-33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）处理，通过抑制ILC2功能消除炎症。条件性HIF-1α缺陷小鼠在IL-33或屋尘螨（HDM）刺激后，ILC2反应和气道炎症减轻。转录组和代谢分析显示，与同窝对照小鼠相比，条件性HIF-1α基因敲除小鼠肺ILC2中的糖酵解显著受损。染色质免疫沉淀结果证实，HIF-1α基因敲除和2-DG处理小鼠中糖酵解相关基因转录下调。此外，哮喘患者中HIF-1α/糖酵解轴激活受损与ILC2下调相关。
HIF-1α/糖酵解轴对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。
