嗜酸性粒细胞介导的抑制和抗IL-5增强哮喘患者浆细胞样树突状细胞干扰素反应
2022/05/17
摘要
背景：病毒诱导的类浆细胞树突状细胞（pDCs）分泌IFNα受到IgE的负调节，并与哮喘恶化有关。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pDCs抗病毒IFN应答的影响，确定抗IL-5/5Rα治疗是否能增强pDCs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pDCs。在上清液中测量IFNα，并收集RNA进行批量RNA测序。接下来，来自8名中重度哮喘患者的纯化pDCs，无论是否接受抗IL-5/5Rα治疗，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pDCs IFNα分泌，且不影响pDCs活性。嗜酸性粒细胞源性神经毒素（EDN）和转化生长因子βTGF-β部分重现了pDCs IFNα的抑制作用。转录组分析显示嗜酸性粒细胞对pDCs 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pDCs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与嗜酸性气道疾病相关的RV呼吸道感染相关的pDCs IFNα反应，这表明嗜酸性粒细胞清除疗法可能通过一种潜在机制降低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：病毒诱导的类浆细胞树突状细胞（pDCs）分泌IFNα受到IgE的负调节，并与哮喘恶化有关。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pDCs抗病毒IFN应答的影响，确定抗IL-5/5Rα治疗是否能增强pDCs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pDCs。在上清液中测量IFNα，并收集RNA进行批量RNA测序。接下来，来自8名中重度哮喘患者的纯化pDCs，无论是否接受抗IL-5/5Rα治疗，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pDCs IFNα分泌，且不影响pDCs活性。嗜酸性粒细胞源性神经毒素（EDN）和转化生长因子βTGF-β部分重现了pDCs IFNα的抑制作用。转录组分析显示嗜酸性粒细胞对pDCs 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pDCs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与嗜酸性气道疾病相关的RV呼吸道感染相关的pDCs IFNα反应，这表明嗜酸性粒细胞清除疗法可能通过一种潜在机制降低RV疾病的严重程度。
(中日友好医院呼吸与危重症医学科 李红雯 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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