鼻病毒感染支气管上皮细胞诱导重症哮喘患者特异性支气管平滑肌细胞迁移
2022/02/28
摘要
背景：重症哮喘患者急性加重频率和支气管平滑肌（BSM）质量均增加。支气管上皮细胞（BE）的鼻病毒（RV）感染是哮喘恶化的主要诱因。活检的组织学分析表明，BE和肥厚性BSM之间的密切关系是判断哮喘严重程度的标准。
目的：我们假设BE的RV感染特异性地增加了哮喘BSM细胞的迁移。
方法：收集86例重症哮喘患者和31例非哮喘患者的血清样本、活检组织或BSM细胞。来自非哮喘受试者的BE细胞在气液界面中培养，并暴露于RV-16。通过趋化性分析，评估BSM细胞在上清液中的迁移情况。通过转录组学和ELISA分析趋化因子浓度。免疫细胞化学、免疫印迹和流式细胞术用于量化CXCR3亚型分布。CXCR3下游信号通路通过钙成像和蛋白质印迹进行评估。
结果：重症哮喘患者的BSM细胞特异性地向RV感染的BE迁移，而非哮喘患者的BSM细胞没有迁移。这种特异性迁移是由BE CXCL10驱动的，它在体外因RV感染而增加，在体内因重症哮喘患者病情加重而增加。其机制与重症哮喘BSM细胞中CXCR3-B特异性亚型的表达和激活降低有关。
结论：我们已经证实了重症哮喘患者RV恶化后BSM重塑的新机制。本研究强调CXCL10/CXCR3-A轴是重症哮喘的潜在治疗靶点。
Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients
Alexis Celle, Pauline Esteves, Guillaume Cardouat, Fabien Beaufils, Edmée Eyraud, Isabelle Dupin, Elise Maurat, Sabrina Lacomme, Olga Ousova, Hugues Begueret, Matthieu Thumerel, Roger Marthan, Pierre-Olivier Girodet, Patrick Berger, Thomas Trian
Abstract
Background: Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma.
Objective: We hypothesized that RV infection of BE specifically increases asthmatic BSM cell migration.
Methods: Serum samples, biopsies or BSM cells were obtained from 86 patients with severe asthma and 31 non-asthmatic subjects. BE cells from non-asthmatic subjects were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. Immunocytochemistry, western blotting and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots.
Results: BSM cells from severe asthmatic patients specifically migrated toward RV-infected BE, whereas those from non-asthmatic subjects did not. This specific migration is driven by BE CXCL10, which was increased in vitro in response to RV infection as well as in vivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B-specific isoform in severe asthmatic BSM cells.
Conclusion: We have demonstrated a novel mechanism of BSM remodeling in severe asthmatic patients following RV exacerbation. This study highlights the CXCL10/CXCR3-A axis as a potential therapeutic target in severe asthma.
背景：重症哮喘患者急性加重频率和支气管平滑肌（BSM）质量均增加。支气管上皮细胞（BE）的鼻病毒（RV）感染是哮喘恶化的主要诱因。活检的组织学分析表明，BE和肥厚性BSM之间的密切关系是判断哮喘严重程度的标准。
目的：我们假设BE的RV感染特异性地增加了哮喘BSM细胞的迁移。
方法：收集86例重症哮喘患者和31例非哮喘患者的血清样本、活检组织或BSM细胞。来自非哮喘受试者的BE细胞在气液界面中培养，并暴露于RV-16。通过趋化性分析，评估BSM细胞在上清液中的迁移情况。通过转录组学和ELISA分析趋化因子浓度。免疫细胞化学、免疫印迹和流式细胞术用于量化CXCR3亚型分布。CXCR3下游信号通路通过钙成像和蛋白质印迹进行评估。
结果：重症哮喘患者的BSM细胞特异性地向RV感染的BE迁移，而非哮喘患者的BSM细胞没有迁移。这种特异性迁移是由BE CXCL10驱动的，它在体外因RV感染而增加，在体内因重症哮喘患者病情加重而增加。其机制与重症哮喘BSM细胞中CXCR3-B特异性亚型的表达和激活降低有关。
结论：我们已经证实了重症哮喘患者RV恶化后BSM重塑的新机制。本研究强调CXCL10/CXCR3-A轴是重症哮喘的潜在治疗靶点。
(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 Feb 7;S0091-6749(22)00148-8. doi: 10.1016/j.jaci.2022.01.022.)
(J Allergy Clin Immunol. 2022 Feb 7;S0091-6749(22)00148-8. doi: 10.1016/j.jaci.2022.01.022.)
Rhinovirus infection of bronchial epithelium induces specific bronchial smooth muscle cell migration of severe asthmatic patients
Alexis Celle, Pauline Esteves, Guillaume Cardouat, Fabien Beaufils, Edmée Eyraud, Isabelle Dupin, Elise Maurat, Sabrina Lacomme, Olga Ousova, Hugues Begueret, Matthieu Thumerel, Roger Marthan, Pierre-Olivier Girodet, Patrick Berger, Thomas Trian
Abstract
Background: Patients with severe asthma show an increase in both exacerbation frequency and bronchial smooth muscle (BSM) mass. Rhinovirus (RV) infection of the bronchial epithelium (BE) is the main trigger of asthma exacerbations. Histological analysis of biopsies shows that a close connection between BE and hypertrophic BSM is a criterion for severity of asthma.
Objective: We hypothesized that RV infection of BE specifically increases asthmatic BSM cell migration.
Methods: Serum samples, biopsies or BSM cells were obtained from 86 patients with severe asthma and 31 non-asthmatic subjects. BE cells from non-asthmatic subjects were cultured in an air-liquid interface and exposed to RV-16. Migration of BSM cells was assessed in response to BE supernatant using chemotaxis assays. Chemokine concentrations were analyzed by transcriptomics and ELISAs. Immunocytochemistry, western blotting and flow cytometry were used to quantify CXCR3 isoform distribution. CXCR3 downstream signaling pathways were assessed by calcium imaging and western blots.
Results: BSM cells from severe asthmatic patients specifically migrated toward RV-infected BE, whereas those from non-asthmatic subjects did not. This specific migration is driven by BE CXCL10, which was increased in vitro in response to RV infection as well as in vivo in serum from exacerbating patients with severe asthma. The mechanism is related to both decreased expression and activation of the CXCR3-B-specific isoform in severe asthmatic BSM cells.
Conclusion: We have demonstrated a novel mechanism of BSM remodeling in severe asthmatic patients following RV exacerbation. This study highlights the CXCL10/CXCR3-A axis as a potential therapeutic target in severe asthma.
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