哮喘患者痰巨噬细胞的活性及多样性：严重程度及炎症表型的作用
2020/08/20
摘要
背景：巨噬细胞调控固有免疫和适应性免疫，但它们在重症哮喘患者中的作用仍不清楚。我们对来自U-BIOPRED队列研究中的104名哮喘患者及16名健康志愿者的痰巨噬细胞亚型的基因特征进行调查。
方法：利用基因集变异分析研究不同刺激巨噬细胞的49个基因特征，其中一个用于评估肺组织固有细胞（TR-Mφ），两个用于极化。变化分析。我们计算了包括严重程度及既往确诊哮喘患者的转录组相关簇（TAC）的富集评分（ES）。
结果：与轻中度哮喘患者及健康志愿者相比，重症哮喘患者巨噬细胞数量明显减少。在重症哮喘患者中，大多数基因ES评分显著降低，除了3个通过NF-κB途径TNF及Toll样受体驱动的炎症反应，通过脂氧合酶途径类花生酸生物合成及IL-2的生物合成（所有p <0.01）。与TAC1和TAC2哮喘患者相比，TAC3组痰巨噬细胞数量及大多数巨噬细胞标志的ES评分更高。 然而，在TAC1中发现了3个模块的高度富集，这些模块显示了与Toll样受体和TNF受体激活以及花生四烯酸代谢相关的炎性途径（p <0.001），在TAC2中存在炎性体和干扰素信号通路（p <0.001）。数据已在ADEPT队列得到验证。与常规M1和M2分类相比，模块分析提供了更多信息。TR-Mφ富含TAC3，并与线粒体功能有关。
结论：重症粒细胞型哮喘患者中巨噬细胞活化下降，强调了固有免疫的缺陷，除了以不同炎症途径为特点的特定亚群。
Sputum macrophage diversity and activation in asthma: role of severity and inflammatory phenotype
Angelica Tiotiu , Nazanin Zounemat Kermani , Yusef Badi , Stelios Pavlidis , Philip M Hansbro , Yi-Ke Guo , Kian Fan Chung , Ian M Adcock , U-BIOPRED consortium project team
Abstract
Background: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort.
Methods: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs).
Results: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p<0.01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll-like and TNF receptor activation and arachidonic acid metabolism (p<0.001) and in TAC2 for the inflammasome- and interferon-signalling pathways (p<0.001).Data was validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR-Mφ were enriched in TAC3 and associated with mitochondrial function.
Conclusions: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterised by distinct inflammatory pathways.
背景：巨噬细胞调控固有免疫和适应性免疫，但它们在重症哮喘患者中的作用仍不清楚。我们对来自U-BIOPRED队列研究中的104名哮喘患者及16名健康志愿者的痰巨噬细胞亚型的基因特征进行调查。
方法：利用基因集变异分析研究不同刺激巨噬细胞的49个基因特征，其中一个用于评估肺组织固有细胞（TR-Mφ），两个用于极化。变化分析。我们计算了包括严重程度及既往确诊哮喘患者的转录组相关簇（TAC）的富集评分（ES）。
结果：与轻中度哮喘患者及健康志愿者相比，重症哮喘患者巨噬细胞数量明显减少。在重症哮喘患者中，大多数基因ES评分显著降低，除了3个通过NF-κB途径TNF及Toll样受体驱动的炎症反应，通过脂氧合酶途径类花生酸生物合成及IL-2的生物合成（所有p <0.01）。与TAC1和TAC2哮喘患者相比，TAC3组痰巨噬细胞数量及大多数巨噬细胞标志的ES评分更高。 然而，在TAC1中发现了3个模块的高度富集，这些模块显示了与Toll样受体和TNF受体激活以及花生四烯酸代谢相关的炎性途径（p <0.001），在TAC2中存在炎性体和干扰素信号通路（p <0.001）。数据已在ADEPT队列得到验证。与常规M1和M2分类相比，模块分析提供了更多信息。TR-Mφ富含TAC3，并与线粒体功能有关。
结论：重症粒细胞型哮喘患者中巨噬细胞活化下降，强调了固有免疫的缺陷，除了以不同炎症途径为特点的特定亚群。
（中日友好医院呼吸与危重症医学科 张鑫 摘译 林江涛 审校）
（Allergy. 2020 Aug 1. doi: 10.1111/all.14535. Online ahead of print.）
（Allergy. 2020 Aug 1. doi: 10.1111/all.14535. Online ahead of print.）
Sputum macrophage diversity and activation in asthma: role of severity and inflammatory phenotype
Angelica Tiotiu , Nazanin Zounemat Kermani , Yusef Badi , Stelios Pavlidis , Philip M Hansbro , Yi-Ke Guo , Kian Fan Chung , Ian M Adcock , U-BIOPRED consortium project team
Abstract
Background: Macrophages control innate and acquired immunity but their role in severe asthma remains ill-defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U-BIOPRED cohort.
Methods: Forty-nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue-resident cells (TR-Mφ) and two for their polarization (classically- and alternatively-activated macrophages: M1 and M2 respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome-associated clusters (TACs).
Results: Macrophage numbers were significantly decreased in severe asthma compared to mild-moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll-like receptors via NF-κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL-2 biosynthesis (all p<0.01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll-like and TNF receptor activation and arachidonic acid metabolism (p<0.001) and in TAC2 for the inflammasome- and interferon-signalling pathways (p<0.001).Data was validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR-Mφ were enriched in TAC3 and associated with mitochondrial function.
Conclusions: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterised by distinct inflammatory pathways.
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组织常驻和循环记忆Th2细胞在过敏性气道疾病中的不同功能
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Mcl-1保护嗜酸性粒细胞免于凋亡并加剧过敏性气道炎症
