IL-33诱导的中性粒细胞炎症和NETosis是鼻病毒引发的哮喘加重的基础
2023/08/28
摘要
背景：鼻病毒诱导的嗜中性粒细胞胞外诱捕网（NETs）导致急性哮喘恶化，然而在这种情况下引发NETosis的分子因素仍然不明确。
目的：在这里，我们试图揭示IL-33的作用，IL-33是一种上皮细胞来源的警报蛋白，在感染反应中迅速释放。
方法：在患有慢性实验性哮喘(CEA)而不是首次接受试验的对照组的小鼠中，鼻病毒接种诱导早期(感染后1天)炎症反应由中性粒细胞、中性粒细胞相关细胞因子(IL-1α、IL-1β、CXCL1)和NETosis主导，随后是2型炎症期(感染后3-7 )，以嗜酸性粒细胞、IL-4水平升高和杯状细胞增生为特征。
结果：值得注意的是，这两个阶段都被HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor)消融，HpARI阻断IL-33的释放和信号传导。外源性IL-33的滴注以PAD4依赖的方式再现了鼻病毒诱导的早期阶段，包括气道黏膜中NETs的增加。体外IL-33刺激来自CEA小鼠的中性粒细胞，而不是首次接受试验的小鼠，发生NETosis，并产生更多的IL-1α/β IL-4和IL-5。在鼻病毒感染的哮喘患者的鼻腔样本中，IL-33水平与中性粒细胞弹性蛋白酶和dsDNA相关。
结论：我们的研究结果表明，IL-33阻断剂通过减少中性粒细胞募集和NETs的下游生成来改善哮喘恶化的严重性。
IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma.
M Curren B, Ahmed T, Howard DR
Abstrast
Background: Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations, however the molecular factors that trigger NETosis in this context remain ill-defined.
Objective：Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection.
Methods: In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1) and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterized by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia.
Results: Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis, and produced greater amounts of IL-1α/β IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA.
Conclusions: Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.
背景：鼻病毒诱导的嗜中性粒细胞胞外诱捕网（NETs）导致急性哮喘恶化，然而在这种情况下引发NETosis的分子因素仍然不明确。
目的：在这里，我们试图揭示IL-33的作用，IL-33是一种上皮细胞来源的警报蛋白，在感染反应中迅速释放。
方法：在患有慢性实验性哮喘(CEA)而不是首次接受试验的对照组的小鼠中，鼻病毒接种诱导早期(感染后1天)炎症反应由中性粒细胞、中性粒细胞相关细胞因子(IL-1α、IL-1β、CXCL1)和NETosis主导，随后是2型炎症期(感染后3-7 )，以嗜酸性粒细胞、IL-4水平升高和杯状细胞增生为特征。
结果：值得注意的是，这两个阶段都被HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor)消融，HpARI阻断IL-33的释放和信号传导。外源性IL-33的滴注以PAD4依赖的方式再现了鼻病毒诱导的早期阶段，包括气道黏膜中NETs的增加。体外IL-33刺激来自CEA小鼠的中性粒细胞，而不是首次接受试验的小鼠，发生NETosis，并产生更多的IL-1α/β IL-4和IL-5。在鼻病毒感染的哮喘患者的鼻腔样本中，IL-33水平与中性粒细胞弹性蛋白酶和dsDNA相关。
结论：我们的研究结果表明，IL-33阻断剂通过减少中性粒细胞募集和NETs的下游生成来改善哮喘恶化的严重性。
(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)
(Mucosal Immunol 2023 Jul 26;doi: 10.1016/j.mucimm.2023.07.002. IF：6.726.)
(Mucosal Immunol 2023 Jul 26;doi: 10.1016/j.mucimm.2023.07.002. IF：6.726.)
IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma.
M Curren B, Ahmed T, Howard DR
Abstrast
Background: Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations, however the molecular factors that trigger NETosis in this context remain ill-defined.
Objective：Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection.
Methods: In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1) and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterized by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia.
Results: Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis, and produced greater amounts of IL-1α/β IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA.
Conclusions: Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.
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