神经调节肽受体介导轻度哮喘患者气道2型先天性淋巴细胞的快速激活
2024/04/24
摘要
背景：在哮喘中，痰2型先天性淋巴细胞（ILC2）在过敏原激发后 7 小时内被激活。神经免疫相互作用介导粘膜界面处的快速宿主反应。在哮喘小鼠模型中，肺 ILC2 共定位于表达神经肽、神经调节素 U （NMU） 和 NMU 的感觉神经元末端，在体外刺激 ILC2 分泌 2 型细胞因子，对警报素具有累加作用。
目的：探讨NMU/NMUR1轴对哮喘患者ILC2早期激活的影响。
方法：轻度哮喘患者(n=8)被纳入稀释剂对照、过敏原吸入刺激研究。流式细胞术检测痰液中NMU受体1 (NMUR1)和T2细胞因子的表达，ELISA检测气道NMU水平。将其与中重度哮喘患者的样本进行比较(n=9)。流式分类纯化和体外扩增ILC2用于功能分析和转录组学分析。
结果：与稀释剂攻击相比，在过敏原刺激后7小时检测到痰液 ILC2 表达 NMUR1 的显着增加，其中大多数 NMUR1（+）ILC2 表达 IL-5/IL-13。轻、中重度哮喘患者痰液NMUR1(1)+ILC2显著高于中重度哮喘患者，且NMUR1(+)ILC2与吸入皮质类固醇剂量呈负相关。与警报素共培养可上调ILC2中的NMUR1，地塞米松可减弱NMUR1。NMU通过ILC2刺激T2细胞因子的表达，6h时的最大值被地米松或丝裂原活化蛋白激酶½，磷酸肌醇3激酶特异性信号抑制剂所消除，但IL-33信号片段MyD88不受影响。
结论：NMU/NMUR1 轴刺激对 ILC2 的快速作用，并且可能是这些细胞在哮喘嗜酸性粒细胞炎症反应中的重要早期激活剂。
Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma.
Xiaotian, Ju, Akimichi, Nagashima
Abstrast
Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro.
Objective：Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma.
Methods: Mild asthmatics (n=8) were enrolled in a diluent-controlled, allergen-inhalation challenge study. Sputum ILC2 expression of NMU receptor 1 (NMUR1) and T2 cytokines were enumerated by flow cytometry and airway NMU levels were assessed by ELISA. This was compared to samples from moderate-severe asthmatics (n=9). Flow sort-purified and ex-vivo expanded ILC2 were used for functional assays and transcriptomic analyses.
Results: Significant increases in sputum ILC2 expressing NMUR1 were detected 7h post- allergen versus diluent challenge where the majority of NMUR1(+)ILC2 expressed IL-5/IL-13. Sputum NMUR(1)+ILC2 were significantly greater in mild versus moderate-severe asthmatics and NMUR1(+)ILC2 correlated inversely with the dose of inhaled corticosteroid in the latter group. Co-culturing with alarmins upregulated NMUR1 in ILC2, which was attenuated by dexamethasone. NMU stimulated T2 cytokine expression by ILC2, maximal at 6h was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase ½, phospho-inositol 3 kinase but not IL-33 signaling moiety MyD88, in vitro.
Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2, and maybe an important early activator of these cells in eosinophilic inflammatory responses in asthma.
背景：在哮喘中，痰2型先天性淋巴细胞（ILC2）在过敏原激发后 7 小时内被激活。神经免疫相互作用介导粘膜界面处的快速宿主反应。在哮喘小鼠模型中，肺 ILC2 共定位于表达神经肽、神经调节素 U （NMU） 和 NMU 的感觉神经元末端，在体外刺激 ILC2 分泌 2 型细胞因子，对警报素具有累加作用。
目的：探讨NMU/NMUR1轴对哮喘患者ILC2早期激活的影响。
方法：轻度哮喘患者(n=8)被纳入稀释剂对照、过敏原吸入刺激研究。流式细胞术检测痰液中NMU受体1 (NMUR1)和T2细胞因子的表达，ELISA检测气道NMU水平。将其与中重度哮喘患者的样本进行比较(n=9)。流式分类纯化和体外扩增ILC2用于功能分析和转录组学分析。
结果：与稀释剂攻击相比，在过敏原刺激后7小时检测到痰液 ILC2 表达 NMUR1 的显着增加，其中大多数 NMUR1（+）ILC2 表达 IL-5/IL-13。轻、中重度哮喘患者痰液NMUR1(1)+ILC2显著高于中重度哮喘患者，且NMUR1(+)ILC2与吸入皮质类固醇剂量呈负相关。与警报素共培养可上调ILC2中的NMUR1，地塞米松可减弱NMUR1。NMU通过ILC2刺激T2细胞因子的表达，6h时的最大值被地米松或丝裂原活化蛋白激酶½，磷酸肌醇3激酶特异性信号抑制剂所消除，但IL-33信号片段MyD88不受影响。
结论：NMU/NMUR1 轴刺激对 ILC2 的快速作用，并且可能是这些细胞在哮喘嗜酸性粒细胞炎症反应中的重要早期激活剂。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Am J Respir Crit Care Med 2024/04/10;doi: 10.1164/rccm.202311-2164OC.IF: 17.452)
(Am J Respir Crit Care Med 2024/04/10;doi: 10.1164/rccm.202311-2164OC.IF: 17.452)
Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma.
Xiaotian, Ju, Akimichi, Nagashima
Abstrast
Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro.
Objective：Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma.
Methods: Mild asthmatics (n=8) were enrolled in a diluent-controlled, allergen-inhalation challenge study. Sputum ILC2 expression of NMU receptor 1 (NMUR1) and T2 cytokines were enumerated by flow cytometry and airway NMU levels were assessed by ELISA. This was compared to samples from moderate-severe asthmatics (n=9). Flow sort-purified and ex-vivo expanded ILC2 were used for functional assays and transcriptomic analyses.
Results: Significant increases in sputum ILC2 expressing NMUR1 were detected 7h post- allergen versus diluent challenge where the majority of NMUR1(+)ILC2 expressed IL-5/IL-13. Sputum NMUR(1)+ILC2 were significantly greater in mild versus moderate-severe asthmatics and NMUR1(+)ILC2 correlated inversely with the dose of inhaled corticosteroid in the latter group. Co-culturing with alarmins upregulated NMUR1 in ILC2, which was attenuated by dexamethasone. NMU stimulated T2 cytokine expression by ILC2, maximal at 6h was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase ½, phospho-inositol 3 kinase but not IL-33 signaling moiety MyD88, in vitro.
Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2, and maybe an important early activator of these cells in eosinophilic inflammatory responses in asthma.
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下调otulin可诱导中性粒细胞性哮喘炎症小体活化
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