TLR3驱动的IFN-β可以拮抗STAT5激活的细胞因子，并抑制肺固有2型免疫反应
2022/04/19
摘要
背景：2型天然淋巴细胞(Group 2 innate lymphoid cells,ILC2)参与粘膜器官2型免疫反应，并与人类各种变态反应性疾病相关。需要研究来了解调控ILC2的分子和通路途径。
目的：本研究的目的是建立一个限制肺固有2型免疫反应的小鼠模型，并研究参与调节肺ILC2的免疫机制。
方法：给BALB/C小鼠注射各种Toll样受体激动剂，鼻内接触真菌变应原链格孢。通过采用基因敲除小鼠、肺细胞培养及肺中分离的ILC2对其机制进行了研究。
结果：聚肌胞苷酸聚或poly (I:C)，能有效抑制对于真菌变应原链格孢的先天2型反应。Poly (I:C)能促进IFN α、-β和-γ的产生，其抑制作用依赖于IFN-α/β受体通路。在抑制肺部ILC2产生2型细胞因子方面，IFN-β比IFN-α的作用强100倍。信号转导和转录激活因子5 (STAT5)可以激活细胞因子，包括IL-2、IL-7和胸腺基质淋巴细胞生成素，但不包括IL-33，在体外促进肺ILC2的生存和增殖，而IFN-β则可以阻断这些作用。IFN-β抑制了对ILC2分化和维持至关重要的转录因子GATA3的表达。
结论：IFN-β可阻断STAT5激活的细胞因子对肺ILC2的影响，并抑制其生存和效应功能。使用IFN-β可能为治疗涉及ILC2的疾病提供一种新的策略。
TLR3-driven IFN-b antagonizes STAT5-activating cytokines and suppresses innate type 2 response in the lung
Tei R, Iijima K, Matsumoto K, et al.
Abstract
BACKGROUND：Group 2 innate lymphoid cells (ILC2s) are involved in type 2 immune responses in mucosal organs and are associated with various allergic diseases in humans. Studies are needed to understand the molecules and pathways that control ILC2s.
OBJECTIVE：The aims of this study were to develop a mouse model that limits the innate type 2 immune response in the lung and to investigate the immunologic mechanisms involved in regulation of lung ILC2s.
METHODS：Naive BALB/c mice were administered various Toll like receptor agonists and exposed intranasally to the fungal allergen Alternaria alternata. The mechanisms were investigated using gene knockout mice as well as cultures of lung cells and isolated lung ILC2s.
RESULTS：Polyinosinic-polycytidylic acid, or poly (I:C), effectively inhibited innate type 2 response to A alternata. Poly (I:C) promoted production of IFN alpha, -beta, and -gamma, and its inhibitory effects were dependent on the IFN-alpha/beta receptor pathway. IFN-beta was 100 times more potent than IFN-alpha at inhibiting type 2 cytokine production by lung ILC2s. Signal transducer and activator of transcription 5 (STAT5)-activating cytokines, including IL-2, IL-7, and thymic stromal lymphopoietin, but not IL-33, promoted survival and proliferation of lung ILC2s in vitro, while IFN-beta blocked these effects. Expression of the transcription factor GATA3, which is critical for differentiation and maintenance of ILC2s, was inhibited by IFN-beta.
CONCLUSIONS：IFN-beta blocks the effects of STAT5-activating cytokines on lung ILC2s and inhibits their survival and effector functions. Administration of IFN-beta may provide a new strategy to treat diseases involving ILC2s.
背景：2型天然淋巴细胞(Group 2 innate lymphoid cells,ILC2)参与粘膜器官2型免疫反应，并与人类各种变态反应性疾病相关。需要研究来了解调控ILC2的分子和通路途径。
目的：本研究的目的是建立一个限制肺固有2型免疫反应的小鼠模型，并研究参与调节肺ILC2的免疫机制。
方法：给BALB/C小鼠注射各种Toll样受体激动剂，鼻内接触真菌变应原链格孢。通过采用基因敲除小鼠、肺细胞培养及肺中分离的ILC2对其机制进行了研究。
结果：聚肌胞苷酸聚或poly (I:C)，能有效抑制对于真菌变应原链格孢的先天2型反应。Poly (I:C)能促进IFN α、-β和-γ的产生，其抑制作用依赖于IFN-α/β受体通路。在抑制肺部ILC2产生2型细胞因子方面，IFN-β比IFN-α的作用强100倍。信号转导和转录激活因子5 (STAT5)可以激活细胞因子，包括IL-2、IL-7和胸腺基质淋巴细胞生成素，但不包括IL-33，在体外促进肺ILC2的生存和增殖，而IFN-β则可以阻断这些作用。IFN-β抑制了对ILC2分化和维持至关重要的转录因子GATA3的表达。
结论：IFN-β可阻断STAT5激活的细胞因子对肺ILC2的影响，并抑制其生存和效应功能。使用IFN-β可能为治疗涉及ILC2的疾病提供一种新的策略。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Journal of Allergy and Clinical Immunology, 2022, 149(3): 1044. doi: 10.1016/j.jaci.2021.07.041）
（Journal of Allergy and Clinical Immunology, 2022, 149(3): 1044. doi: 10.1016/j.jaci.2021.07.041）
TLR3-driven IFN-b antagonizes STAT5-activating cytokines and suppresses innate type 2 response in the lung
Tei R, Iijima K, Matsumoto K, et al.
Abstract
BACKGROUND：Group 2 innate lymphoid cells (ILC2s) are involved in type 2 immune responses in mucosal organs and are associated with various allergic diseases in humans. Studies are needed to understand the molecules and pathways that control ILC2s.
OBJECTIVE：The aims of this study were to develop a mouse model that limits the innate type 2 immune response in the lung and to investigate the immunologic mechanisms involved in regulation of lung ILC2s.
METHODS：Naive BALB/c mice were administered various Toll like receptor agonists and exposed intranasally to the fungal allergen Alternaria alternata. The mechanisms were investigated using gene knockout mice as well as cultures of lung cells and isolated lung ILC2s.
RESULTS：Polyinosinic-polycytidylic acid, or poly (I:C), effectively inhibited innate type 2 response to A alternata. Poly (I:C) promoted production of IFN alpha, -beta, and -gamma, and its inhibitory effects were dependent on the IFN-alpha/beta receptor pathway. IFN-beta was 100 times more potent than IFN-alpha at inhibiting type 2 cytokine production by lung ILC2s. Signal transducer and activator of transcription 5 (STAT5)-activating cytokines, including IL-2, IL-7, and thymic stromal lymphopoietin, but not IL-33, promoted survival and proliferation of lung ILC2s in vitro, while IFN-beta blocked these effects. Expression of the transcription factor GATA3, which is critical for differentiation and maintenance of ILC2s, was inhibited by IFN-beta.
CONCLUSIONS：IFN-beta blocks the effects of STAT5-activating cytokines on lung ILC2s and inhibits their survival and effector functions. Administration of IFN-beta may provide a new strategy to treat diseases involving ILC2s.
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