哮喘患者中嗜酸性粒细胞抑制而抗IL-5增强浆细胞样树突状细胞的干扰素反应
2022/05/17
摘要
背景：病毒诱导的浆细胞样树突状细胞（pDC）分泌IFNα受到IgE的负调控，并与哮喘发作有关。嗜酸性粒细胞是导致2型（T2）炎症的另一个因素，也与哮喘的严重程度有关。
目的：研究嗜酸性粒细胞对pDC抗病毒IFN应答的影响，确定抗IL-5/5Rα治疗是否能增强pDC抗病毒功能。
方法：在有或无嗜酸性粒细胞/嗜酸性粒细胞上清液的情况下，用鼻病毒-16（RV）体外刺激匿名献血者的血液pDC。在上清液中测量IFNα，并收集RNA进行批量RNA测序。接下来，将8名中重度哮喘患者（接受或不接受抗IL-5/5Rα治疗）血中纯化的pDC在有或没有RV的情况下进行体外培养；比较各组间IFNα分泌和差异基因表达分析。
结果：暴露于嗜酸性粒细胞或嗜酸性粒细胞上清液以剂量依赖性方式抑制鼻病毒（RV）诱导的pDC IFNα分泌，且不影响pDC活性。嗜酸性粒细胞源性神经毒素（EDN）和转化生长因子β即TGF-β部分重现了pDC IFNα的抑制作用。转录组分析显示嗜酸性粒细胞对pDC IFN应答模式的整体抑制，最显著的是干扰素刺激基因（ISG）的基础表达。在接受抗IL-5/5Rα治疗的参与者的pDC中检测到RV诱导的IFNα分泌和转录增加，以及基础ISG表达增加。
结论：我们的研究结果强调了一种新的机制，即T2炎症通过该机制调节嗜酸性气道疾病背景下的RV呼吸道感染相关的pDC IFNα反应，这表明嗜酸性粒细胞清除疗法可能通过这种潜在机制降低RV疾病的严重程度。
Eosinophil-mediated suppression and Anti-IL-5 enhancement of plasmacytoid dendritic cell interferon responses in asthma
Kimberly A Dill-McFarland, Justin T Schwartz, Hongfang Zhao, Baomei Shao, Patricia C Fulkerson, Matthew C Altman, Michelle A Gill
Abstract
Background：Virus-induced IFNα secretion by plasmacytoid dendritic cells (pDCs) is negatively impacted by IgE and has been linked to asthma exacerbations. Eosinophils, another contributor to Type 2 (T2) inflammation, are also associated with asthma severity.
Objective：To investigate the impact of eosinophils on pDC antiviral IFN responses and determine whether anti-IL-5/5Rα therapy enhances pDC antiviral function.
Methods：Blood pDCs purified from anonymous donors were stimulated in vitro with rhinovirus-16 (RV) in the presence or absence of eosinophils/eosinophil supernatants. IFNα was measured in supernatants and RNA collected for bulk RNA-sequencing. Next, purified pDCs from 8 individuals with moderate-severe asthma, treated or not treated with anti-IL-5/5Rα therapy, were cultured ex vivo with or without RV; IFNα secretion and differential gene expression analysis was compared between groups.
Results：Exposure to either eosinophils or eosinophil supernatants inhibited rhinovirus (RV)-induced pDC IFNα secretion in a dose-dependent manner and did not impact pDC viability. Eosinophil-derived neurotoxin (EDN) and transforming growth factor beta TGF-β partially recapitulated pDC IFNα inhibition. Transcriptome analysis revealed global repression of pDC IFN response patterns by eosinophils, most notably in basal expression of interferon stimulated genes (ISGs). Increased RV-induced IFNα secretion and transcription as well as increased basal ISG expression was detected in pDCs from participants treated with anti-IL-5/5Rα therapy.
Conclusion：Our findings highlight a novel mechanism through which T2 inflammation regulates pDC IFNα responses relevant to RV respiratory infections in the context of eosinophilic airway disease, suggesting one potential mechanism through which eosinophil-depleting therapies may reduce severity of RV illnesses.
背景：病毒诱导的浆细胞样树突状细胞（pDC）分泌IFNα受到IgE的负调控，并与哮喘发作有关。嗜酸性粒细胞是导致2型（T2）炎症的另一个因素，也与哮喘的严重程度有关。
目的：研究嗜酸性粒细胞对pDC抗病毒IFN应答的影响，确定抗IL-5/5Rα治疗是否能增强pDC抗病毒功能。
方法：在有或无嗜酸性粒细胞/嗜酸性粒细胞上清液的情况下，用鼻病毒-16（RV）体外刺激匿名献血者的血液pDC。在上清液中测量IFNα，并收集RNA进行批量RNA测序。接下来，将8名中重度哮喘患者（接受或不接受抗IL-5/5Rα治疗）血中纯化的pDC在有或没有RV的情况下进行体外培养；比较各组间IFNα分泌和差异基因表达分析。
结果：暴露于嗜酸性粒细胞或嗜酸性粒细胞上清液以剂量依赖性方式抑制鼻病毒（RV）诱导的pDC IFNα分泌，且不影响pDC活性。嗜酸性粒细胞源性神经毒素（EDN）和转化生长因子β即TGF-β部分重现了pDC IFNα的抑制作用。转录组分析显示嗜酸性粒细胞对pDC IFN应答模式的整体抑制，最显著的是干扰素刺激基因（ISG）的基础表达。在接受抗IL-5/5Rα治疗的参与者的pDC中检测到RV诱导的IFNα分泌和转录增加，以及基础ISG表达增加。
结论：我们的研究结果强调了一种新的机制，即T2炎症通过该机制调节嗜酸性气道疾病背景下的RV呼吸道感染相关的pDC IFNα反应，这表明嗜酸性粒细胞清除疗法可能通过这种潜在机制降低RV疾病的严重程度。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2022 Apr 9;S0091-6749(22)00447-X. doi: 10.1016/j.jaci.2022.03.025.)
(J Allergy Clin Immunol. 2022 Apr 9;S0091-6749(22)00447-X. doi: 10.1016/j.jaci.2022.03.025.)
Eosinophil-mediated suppression and Anti-IL-5 enhancement of plasmacytoid dendritic cell interferon responses in asthma
Kimberly A Dill-McFarland, Justin T Schwartz, Hongfang Zhao, Baomei Shao, Patricia C Fulkerson, Matthew C Altman, Michelle A Gill
Abstract
Background：Virus-induced IFNα secretion by plasmacytoid dendritic cells (pDCs) is negatively impacted by IgE and has been linked to asthma exacerbations. Eosinophils, another contributor to Type 2 (T2) inflammation, are also associated with asthma severity.
Objective：To investigate the impact of eosinophils on pDC antiviral IFN responses and determine whether anti-IL-5/5Rα therapy enhances pDC antiviral function.
Methods：Blood pDCs purified from anonymous donors were stimulated in vitro with rhinovirus-16 (RV) in the presence or absence of eosinophils/eosinophil supernatants. IFNα was measured in supernatants and RNA collected for bulk RNA-sequencing. Next, purified pDCs from 8 individuals with moderate-severe asthma, treated or not treated with anti-IL-5/5Rα therapy, were cultured ex vivo with or without RV; IFNα secretion and differential gene expression analysis was compared between groups.
Results：Exposure to either eosinophils or eosinophil supernatants inhibited rhinovirus (RV)-induced pDC IFNα secretion in a dose-dependent manner and did not impact pDC viability. Eosinophil-derived neurotoxin (EDN) and transforming growth factor beta TGF-β partially recapitulated pDC IFNα inhibition. Transcriptome analysis revealed global repression of pDC IFN response patterns by eosinophils, most notably in basal expression of interferon stimulated genes (ISGs). Increased RV-induced IFNα secretion and transcription as well as increased basal ISG expression was detected in pDCs from participants treated with anti-IL-5/5Rα therapy.
Conclusion：Our findings highlight a novel mechanism through which T2 inflammation regulates pDC IFNα responses relevant to RV respiratory infections in the context of eosinophilic airway disease, suggesting one potential mechanism through which eosinophil-depleting therapies may reduce severity of RV illnesses.
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芝麻素通过调节线粒体自噬和线粒体凋亡减轻哮喘气道炎症
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哮喘支气管平滑肌增加鼻病毒在支气管上皮内的复制
