TL1A/DR3轴在嗜酸性粒细胞性哮喘患者ILC2s活化中的作用
2021/08/24
摘要
背景：2型固有淋巴细胞（ILC2s）是2型炎症的关键细胞。在小鼠哮喘模型中，一些ILC2s在缺乏上皮源性细胞因子信号的情况下仍然可被激活，这意味着存在交替的刺激途径。死亡受体3（DR3）是肿瘤坏死因子受体超级家族的一员，在ILC2s上表达，全基因组关联研究报道DR3配体、TNF样蛋白1A(TL1A)与慢性炎症之间存在关联性。
目的：我们研究了嗜酸性粒细胞性哮喘气道ILC2生物学方面TL1A/DR3轴的变化。
方法：对稳定的轻度哮喘患者进行变应原吸入试验，并评估痰细胞中DR3的表达。我们研究了细胞因子对ILC2s上DR3表达的调节和类固醇的敏感性。在轻度哮喘患者和强的松以依赖的重度嗜酸性粒细胞性哮喘患者的痰中评估气道TL1A。
测量指标及主要结果：在体外，IL-2，IL-33或TSLP可显著上调痰中过敏原刺激后24小时的DR3+ILC2S和DR3在ILC2S上的表达。TL1A刺激可显著增加ILC2S的IL-5表达，但可被地塞米松减弱；这是一种当TSLP存在时无效的作用。轻度哮喘患者在过敏原刺激后24小时气道TL1A水平升高，严重嗜酸性哮喘患者中则会显著升高。在有气道自身免疫反应的重度哮喘患者中可检测到最高水平的反应。高自身抗体水平的重度哮喘患者痰中C1q+免疫复合物刺激单核细胞产生TL1A。
结论：哮喘中TL1A/DR3轴是ILC2s的共同刺激因子，特别是在易出现自身免疫反应患者的气道中。
The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma
Kentaro Machida, Michael Aw, Brittany M A Salter, Xiaotian Ju, Manali Mukherjee , Gail M Gauvreau, Paul M O'Byrne, Parameswaran Nair , Roma Sehmi
Abstract
Rationale:Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions.
Objectives:We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma.
Methods: Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma.
Measurements and Main Results:There was a significant increase in sputum DR3+ ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP in vitro. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q+ immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes.
Conclusions:The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
背景：2型固有淋巴细胞（ILC2s）是2型炎症的关键细胞。在小鼠哮喘模型中，一些ILC2s在缺乏上皮源性细胞因子信号的情况下仍然可被激活，这意味着存在交替的刺激途径。死亡受体3（DR3）是肿瘤坏死因子受体超级家族的一员，在ILC2s上表达，全基因组关联研究报道DR3配体、TNF样蛋白1A(TL1A)与慢性炎症之间存在关联性。
目的：我们研究了嗜酸性粒细胞性哮喘气道ILC2生物学方面TL1A/DR3轴的变化。
方法：对稳定的轻度哮喘患者进行变应原吸入试验，并评估痰细胞中DR3的表达。我们研究了细胞因子对ILC2s上DR3表达的调节和类固醇的敏感性。在轻度哮喘患者和强的松以依赖的重度嗜酸性粒细胞性哮喘患者的痰中评估气道TL1A。
测量指标及主要结果：在体外，IL-2，IL-33或TSLP可显著上调痰中过敏原刺激后24小时的DR3+ILC2S和DR3在ILC2S上的表达。TL1A刺激可显著增加ILC2S的IL-5表达，但可被地塞米松减弱；这是一种当TSLP存在时无效的作用。轻度哮喘患者在过敏原刺激后24小时气道TL1A水平升高，严重嗜酸性哮喘患者中则会显著升高。在有气道自身免疫反应的重度哮喘患者中可检测到最高水平的反应。高自身抗体水平的重度哮喘患者痰中C1q+免疫复合物刺激单核细胞产生TL1A。
结论：哮喘中TL1A/DR3轴是ILC2s的共同刺激因子，特别是在易出现自身免疫反应患者的气道中。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2020 Oct 15;202(8):1105-1114. doi: 10.1164/rccm.201909-1722OC)
(Am J Respir Crit Care Med. 2020 Oct 15;202(8):1105-1114. doi: 10.1164/rccm.201909-1722OC)
The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma
Kentaro Machida, Michael Aw, Brittany M A Salter, Xiaotian Ju, Manali Mukherjee , Gail M Gauvreau, Paul M O'Byrne, Parameswaran Nair , Roma Sehmi
Abstract
Rationale:Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial cell-derived cytokine signaling, implicating alternate stimulatory pathways. DR3 (death receptor 3), a member of the tumor necrosis factor receptor superfamily, is expressed on ILC2s. Genome-wide association studies report an association between DR3 ligand, TL1A (tumor necrosis factor-like protein 1A), and chronic inflammatory conditions.
Objectives:We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma.
Methods: Stable subjects with mild asthma were subject to allergen inhalation challenge, and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from subjects with mild asthma and subjects with prednisone-dependent severe eosinophilic asthma.
Measurements and Main Results:There was a significant increase in sputum DR3+ ILC2s 24 hours after allergen challenge, and DR3 expression on ILC2s was upregulated by IL-2, IL-33, or TSLP in vitro. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and was attenuated by dexamethasone, an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 hours after allergen challenge in subjects with mild asthma but were significantly greater in those with severe eosinophilic asthma. The highest levels were detected in subjects with severe asthma with airway autoimmune responses. C1q+ immune complexes from the sputa of subjects with severe asthma with high autoantibody levels stimulated TL1A production by monocytes.
Conclusions:The TL1A/DR3 axis is a costimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
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鼻病毒诱发哮喘急性加重时的肺固有淋巴细胞反应：一项临床试验
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早期鼻腔微生物群的纵向变化与儿童哮喘的风险
