一种常见的IL-4受体突变通过Treg细胞GRB2-IL-6-Notch4通路加重哮喘
2022/11/22
摘要
背景：遗传和环境因素相互作用促进哮喘的机制尚不清楚。白介素-4受体α链R576（IL-4RαR576）突变和Notch4均依赖IL-6破坏肺调节性T（Treg）细胞，进而引起变应原和环境污染物颗粒诱导的支气管哮喘肺部炎症。
目的：本研究旨在检验IL-4RαR576和Notch4在促进哮喘炎症中的相互作用。
方法：本研究分析了哮喘患者外周血单个核细胞（PBMC）的T辅助2型细胞因子的产生和Treg细胞Notch4的表达以代表IL4RR576等位基因的功能。在遗传小鼠模型中进一步分析了IL-4RαR576可上调Treg细胞上Notch4的表达劲儿促进严重过敏性气道炎症。
结果：携带IL4RR576等位基因的哮喘患者的循环Treg细胞表达Notch4增加，表明了疾病的严重程度和血清IL-6的功能情况。携带Il4raR576等位基因的小鼠表现出更为严重的Notch4依赖的过敏性气道炎症，这在Treg特异性Notch4缺失或用抗Notch4抗体治疗时受到抑制。IL-4RαR576介导的信号通路可上调肺Treg细胞中Notch4及其下游介质Yap1和β-catenin的表达，进而加重肺部炎症。这一上调过程依赖于生长因子受体结合蛋白2（GRB2）和IL-6受体。
结论：上述结果明确了IL-4RαR576调控的GRB2-IL-6-Notch4信号通路，可通过破坏肺Treg细胞功能加重哮喘。
A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit.
Benamar M, Harb H, Chen Q, Wang M, Chan TMF, Fong J, Phipatanakul W, Cunningham A, Ertem D, Petty CR, Mousavi AJ, Sioutas C, Crestani E, Chatila TA.
Abstract
BACKGROUND:The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (Treg ) cells in an IL-6-dependent manner.
OBJECTIVES: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation.
METHODS:Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models.
RESULTS:Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor.
CONCLUSIONS:These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.
背景：遗传和环境因素相互作用促进哮喘的机制尚不清楚。白介素-4受体α链R576（IL-4RαR576）突变和Notch4均依赖IL-6破坏肺调节性T（Treg）细胞，进而引起变应原和环境污染物颗粒诱导的支气管哮喘肺部炎症。
目的：本研究旨在检验IL-4RαR576和Notch4在促进哮喘炎症中的相互作用。
方法：本研究分析了哮喘患者外周血单个核细胞（PBMC）的T辅助2型细胞因子的产生和Treg细胞Notch4的表达以代表IL4RR576等位基因的功能。在遗传小鼠模型中进一步分析了IL-4RαR576可上调Treg细胞上Notch4的表达劲儿促进严重过敏性气道炎症。
结果：携带IL4RR576等位基因的哮喘患者的循环Treg细胞表达Notch4增加，表明了疾病的严重程度和血清IL-6的功能情况。携带Il4raR576等位基因的小鼠表现出更为严重的Notch4依赖的过敏性气道炎症，这在Treg特异性Notch4缺失或用抗Notch4抗体治疗时受到抑制。IL-4RαR576介导的信号通路可上调肺Treg细胞中Notch4及其下游介质Yap1和β-catenin的表达，进而加重肺部炎症。这一上调过程依赖于生长因子受体结合蛋白2（GRB2）和IL-6受体。
结论：上述结果明确了IL-4RαR576调控的GRB2-IL-6-Notch4信号通路，可通过破坏肺Treg细胞功能加重哮喘。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Allergy. 2022 Nov;77(11):3377-3387. doi: 10.1111/all.15444.)
(Allergy. 2022 Nov;77(11):3377-3387. doi: 10.1111/all.15444.)
A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit.
Benamar M, Harb H, Chen Q, Wang M, Chan TMF, Fong J, Phipatanakul W, Cunningham A, Ertem D, Petty CR, Mousavi AJ, Sioutas C, Crestani E, Chatila TA.
Abstract
BACKGROUND:The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (Treg ) cells in an IL-6-dependent manner.
OBJECTIVES: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation.
METHODS:Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models.
RESULTS:Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor.
CONCLUSIONS:These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.
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气道上皮细胞特异性递送脂质纳米颗粒负载siRNA用于哮喘治疗
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重症哮喘患者呼吸道感染自身抗体介导的巨噬细胞功能障碍
