缺氧诱导因子2α通过调节磷脂代谢促进干细胞样Th2细胞的致病极化
2025/01/26
摘要
T辅助2（Th2）细胞协调针对寄生虫感染的免疫，促进组织修复，促进哮喘和组织纤维化的病理。在这里，我们研究了驱动Th2细胞致病分化的机制。哮喘和慢性鼻窦炎患者CD4 T细胞的单细胞分析显示，Th2细胞中缺氧诱导因子（HIF）2α的高表达。在小鼠中，HIF2α缺乏会损害Th2分化并减轻哮喘炎症。单细胞和谱系追踪方法描绘了从TCF1Ly108干细胞样Th2细胞到ST2CD25致病子代的分化轨迹，这取决于HIF2α-GATA3回路，该回路通过肌醇多磷酸多激酶（IPMK）的转录调节调节磷脂代谢和T细胞受体（TCR）-磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（AKT）的激活。HIF2α缺陷细胞中IPMK的过表达促进了磷脂酰肌醇（3,4,5）-三磷酸（PIP+++3）的合成和致病性Th2细胞的分化，而HIF2α的药理学抑制损害了Th2细胞致病性的分化并减轻了气道炎症。我们的研究结果提供了促进Th2介导病理的背景线索，并表明HIF2α是哮喘的治疗靶点。
Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism
Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang
Abstract
T helper 2 (Th2) cells orchestrate immunity against parasite infection and promote tissue repair but promote pathology in asthma and tissue fibrosis. Here, we examined the mechanisms driving pathogenic differentiation of Th2 cells. Single-cell analyses of CD4 T cells from asthma and chronic rhinosinusitis patients revealed high expression of the hypoxia-inducible factor (HIF)2α in Th2 cells. In mice, HIF2α deficiency impaired Th2 differentiation and alleviated asthmatic inflammation. Single-cell and lineage tracing approaches delineated a differentiation trajectory from TCF1Ly108 stem-like Th2 cells to the ST2CD25 pathogenic progeny, depending on a HIF2α-GATA3 circuit that modulated phospholipid metabolism and T cell receptor (TCR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) activation via transcriptional regulation of the inositol polyphosphate multikinase (IPMK). Overexpression of IPMK in HIF2α-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP+++++3) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2α impaired pathogenic differentiation of Th2 cells and mitigated airway inflammation. Our findings provide insight into the contextual cues that promote Th2-mediated pathology and suggest HIF2α as a therapeutic target in asthma.
T辅助2（Th2）细胞协调针对寄生虫感染的免疫，促进组织修复，促进哮喘和组织纤维化的病理。在这里，我们研究了驱动Th2细胞致病分化的机制。哮喘和慢性鼻窦炎患者CD4 T细胞的单细胞分析显示，Th2细胞中缺氧诱导因子（HIF）2α的高表达。在小鼠中，HIF2α缺乏会损害Th2分化并减轻哮喘炎症。单细胞和谱系追踪方法描绘了从TCF1Ly108干细胞样Th2细胞到ST2CD25致病子代的分化轨迹，这取决于HIF2α-GATA3回路，该回路通过肌醇多磷酸多激酶（IPMK）的转录调节调节磷脂代谢和T细胞受体（TCR）-磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（AKT）的激活。HIF2α缺陷细胞中IPMK的过表达促进了磷脂酰肌醇（3,4,5）-三磷酸（PIP+++3）的合成和致病性Th2细胞的分化，而HIF2α的药理学抑制损害了Th2细胞致病性的分化并减轻了气道炎症。我们的研究结果提供了促进Th2介导病理的背景线索，并表明HIF2α是哮喘的治疗靶点。
(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)
(Immunity. 2024 Nov 21:S1074-7613(24)00496-5.)
(Immunity. 2024 Nov 21:S1074-7613(24)00496-5.)
Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism
Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang
Abstract
T helper 2 (Th2) cells orchestrate immunity against parasite infection and promote tissue repair but promote pathology in asthma and tissue fibrosis. Here, we examined the mechanisms driving pathogenic differentiation of Th2 cells. Single-cell analyses of CD4 T cells from asthma and chronic rhinosinusitis patients revealed high expression of the hypoxia-inducible factor (HIF)2α in Th2 cells. In mice, HIF2α deficiency impaired Th2 differentiation and alleviated asthmatic inflammation. Single-cell and lineage tracing approaches delineated a differentiation trajectory from TCF1Ly108 stem-like Th2 cells to the ST2CD25 pathogenic progeny, depending on a HIF2α-GATA3 circuit that modulated phospholipid metabolism and T cell receptor (TCR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) activation via transcriptional regulation of the inositol polyphosphate multikinase (IPMK). Overexpression of IPMK in HIF2α-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP+++++3) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2α impaired pathogenic differentiation of Th2 cells and mitigated airway inflammation. Our findings provide insight into the contextual cues that promote Th2-mediated pathology and suggest HIF2α as a therapeutic target in asthma.
上一篇：
CC16通过抑制铁突变减轻PM2.5诱导的哮喘小鼠肺上皮细胞损伤和气道炎症
下一篇：
miR-15b-5p通过HMGB1/TLR4/IL-33信号轴缓解哮喘气道重构的作用机制
