在重症哮喘患者中，嗜酸性粒细胞外网状陷阱通过刺激气道上皮活化2型固有淋巴细胞
2019/08/27
摘要
背景：活化的嗜酸细胞释放细胞外网状陷阱（EETs），这促进了重症哮喘（SA）气道炎症的产生。然而，EETs在固有免疫中的作用尚未完全确定。本研究旨在探讨EETS介导的重症哮喘气道炎症机制。
方法：对重症哮喘（n=13）、非重症哮喘（NSA，n=17）、健康对照（HC，n=8）患者的EET+嗜酸性粒细胞和2型固有淋巴细胞（ILC2s）的外周计数进行评估。为了证实EETS的作用，对小鼠进行气道高反应性（AHR）和适应性/固有免疫反应评估。此外，还检测了抗IL-33/TSLP抗体的作用。
结果：SA中EET+嗜酸性粒细胞和ILC2s的数量显著升高，这两个细胞之间呈正相关（r=0.539，P<0.001）。当予小鼠注射EETs时，我们观察到支气管肺泡灌洗液（BALF）中上皮细胞源性细胞因子（IL-1α、IL-1β、CXCL -1、CCL24, IL-33, and TSLP）和嗜酸性粒细胞/中性粒细胞计数显著增加，且肺泡灌洗液（BALF）中产生IL-5或IL-13的ILC2s比例增加。予接受ILC2s的Rag1-/-小鼠EETS治疗时，发现BALF中的AHR和IL-5/IL-13水平升高，并可被抗IL-33或抗TSLP抗体有效抑制。
结论：EETs可增强重症哮喘患者的固有和2型免疫应答，其上皮靶向生物制剂（抗IL-33/TSLP抗体）可能具有潜在的疗效。
Eosinophil extracellular traps activate type 2 innate lymphoid cells through stimulating airway epithelium in severe asthma.
Choi Y, Kim YM, Lee HR, Mun J, Sim S, Lee DH, Duy PL, Kim SH, Shin YS, Lee SW, Park HS.
Abstract
BACKGROUND: Activated eosinophils release extracellular traps (EETs), which contribute to airway inflammation in severe asthma (SA). However, the role of EETs in innate immunity has not yet been completely determined. The present study aimed to demonstrate the mechanism of airway inflammation in SA mediated by EETs.
METHODS: Peripheral counts of EET+ eosinophils and type 2 innate lymphoid cells (ILC2s) were evaluated in patients with SA (n = 13), nonsevere asthma (NSA, n = 17), and healthy control subjects (HC, n = 8). To confirm the effect of EETs, airway hyperresponsiveness (AHR) and adapted/innate immune responses were assessed in mice. Furthermore, the effects of anti-IL-33/TSLP antibody were tested.
RESULTS: The numbers of EET+ eosinophils and ILC2s were significantly elevated in SA, with a positive correlation between these 2 cells (r = .539, P < .001). When mice were injected with EETs, we observed significant increases in epithelium-derived cytokines (IL-1α, IL-1β, CXCL-1, CCL24, IL-33, and TSLP) and eosinophil/neutrophil count in bronchoalveolar lavage fluid (BALF) as well as an increased proportion of IL-5 or IL-13-producing ILC2s in the lungs. When Rag1-/- mice receiving ILC2s were treated with EETs, increased AHR and IL-5/IL-13 levels in BALF were noted, which were effectively suppressed by anti-IL-33 or anti-TSLP antibody.
CONCLUSION: EETs could enhance innate and type 2 immune responses in SA, in which epithelium-targeting biologics (anti-IL-33/TSLP antibody) may have a potential benefit. This article is protected by copyright. All rights reserved.
背景：活化的嗜酸细胞释放细胞外网状陷阱（EETs），这促进了重症哮喘（SA）气道炎症的产生。然而，EETs在固有免疫中的作用尚未完全确定。本研究旨在探讨EETS介导的重症哮喘气道炎症机制。
方法：对重症哮喘（n=13）、非重症哮喘（NSA，n=17）、健康对照（HC，n=8）患者的EET+嗜酸性粒细胞和2型固有淋巴细胞（ILC2s）的外周计数进行评估。为了证实EETS的作用，对小鼠进行气道高反应性（AHR）和适应性/固有免疫反应评估。此外，还检测了抗IL-33/TSLP抗体的作用。
结果：SA中EET+嗜酸性粒细胞和ILC2s的数量显著升高，这两个细胞之间呈正相关（r=0.539，P<0.001）。当予小鼠注射EETs时，我们观察到支气管肺泡灌洗液（BALF）中上皮细胞源性细胞因子（IL-1α、IL-1β、CXCL -1、CCL24, IL-33, and TSLP）和嗜酸性粒细胞/中性粒细胞计数显著增加，且肺泡灌洗液（BALF）中产生IL-5或IL-13的ILC2s比例增加。予接受ILC2s的Rag1-/-小鼠EETS治疗时，发现BALF中的AHR和IL-5/IL-13水平升高，并可被抗IL-33或抗TSLP抗体有效抑制。
结论：EETs可增强重症哮喘患者的固有和2型免疫应答，其上皮靶向生物制剂（抗IL-33/TSLP抗体）可能具有潜在的疗效。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Allergy. 2019 Jul 22. doi: 10.1111/all.13997.)
(Allergy. 2019 Jul 22. doi: 10.1111/all.13997.)
Eosinophil extracellular traps activate type 2 innate lymphoid cells through stimulating airway epithelium in severe asthma.
Choi Y, Kim YM, Lee HR, Mun J, Sim S, Lee DH, Duy PL, Kim SH, Shin YS, Lee SW, Park HS.
Abstract
BACKGROUND: Activated eosinophils release extracellular traps (EETs), which contribute to airway inflammation in severe asthma (SA). However, the role of EETs in innate immunity has not yet been completely determined. The present study aimed to demonstrate the mechanism of airway inflammation in SA mediated by EETs.
METHODS: Peripheral counts of EET+ eosinophils and type 2 innate lymphoid cells (ILC2s) were evaluated in patients with SA (n = 13), nonsevere asthma (NSA, n = 17), and healthy control subjects (HC, n = 8). To confirm the effect of EETs, airway hyperresponsiveness (AHR) and adapted/innate immune responses were assessed in mice. Furthermore, the effects of anti-IL-33/TSLP antibody were tested.
RESULTS: The numbers of EET+ eosinophils and ILC2s were significantly elevated in SA, with a positive correlation between these 2 cells (r = .539, P < .001). When mice were injected with EETs, we observed significant increases in epithelium-derived cytokines (IL-1α, IL-1β, CXCL-1, CCL24, IL-33, and TSLP) and eosinophil/neutrophil count in bronchoalveolar lavage fluid (BALF) as well as an increased proportion of IL-5 or IL-13-producing ILC2s in the lungs. When Rag1-/- mice receiving ILC2s were treated with EETs, increased AHR and IL-5/IL-13 levels in BALF were noted, which were effectively suppressed by anti-IL-33 or anti-TSLP antibody.
CONCLUSION: EETs could enhance innate and type 2 immune responses in SA, in which epithelium-targeting biologics (anti-IL-33/TSLP antibody) may have a potential benefit. This article is protected by copyright. All rights reserved.
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