黄体微球菌衍生的细胞外囊泡通过调节气道上皮细胞中的miRNA来减轻中性粒细胞性哮喘
2023/02/01
摘要
细菌胞外小泡（EV）已被证明可以调节各种肺部疾病，但其在哮喘中的作用仍不确定。为了证明黄体微球菌衍生EVs（MlEV）在哮喘中的临床意义，我们招募了45名哮喘患者（20名中性粒细胞性哮喘[NA]患者，25名嗜酸性粒细胞哮喘[EA]患者）和40名健康对照（HC）。当通过ELISA评估血清中MlEV特异性IgG1和IgG4的患病率时，哮喘患者中的MlEV特异性IgG4（而非IgG1）水平低于HC。在哮喘患者中，NA患者的MIEV特异性IgG4水平显著低于EA患者。此外，血清MlEV特异性IgG4水平与FEV1（%）值呈正相关。在哮喘C57BL/6小鼠中，MlEVs通过减少支气管肺泡灌洗液中IL-1β和IL-17的产生以及肺组织中第3组固有淋巴细胞（ILC3s）的数量，显著减轻中性粒细胞气道炎症。为了阐明MlEVs在NA中的功能机制，体外研究了MlEVs对气道上皮细胞（AECs）和免疫细胞的影响。根据微阵列分析，MlEV上调了AECs中hsa-miR-4517的表达。此外，这种miRNA可以抑制单核细胞产生IL-1β，从而抑制ILC3的活化和中性粒细胞的募集。这些发现表明，MlEVs可能是一种新的治疗剂，通过调节AECs中miRNA的表达来管理未解决的NA。
Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells
Soyoon Sim, Dong-Hyun Lee, Kwang-Sun Kim, Hyeon Ju Park, Yoon-Keun Kim, Youngwoo Choi, Hae-Sim Park
Abstract
Bacterial extracellular vesicles (EVs) have been shown to regulate various pulmonary diseases, but their functions in asthma remain uncertain. To demonstrate the clinical significance of Micrococcus luteus-derived EVs (MlEVs) in asthma, we enrolled 45 asthmatic patients (20 patients with neutrophilic asthma [NA], 25 patients with eosinophilic asthma [EA]) and 40 healthy controls (HCs). When the prevalence of IgG1 and IgG4 specific to MlEVs was evaluated in serum by ELISA, lower levels of MlEV-specific IgG4 (but not IgG1) were noted in asthmatic patients than in HCs. Among asthmatic patients, significantly lower levels of MIEV-specific IgG4 were noted in patients with NA than in those with EA. Moreover, there was a positive correlation between serum MlEV-specific IgG4 levels and FEV1 (%) values. In asthmatic C57BL/6 mice, MlEVs significantly attenuated neutrophilic airway inflammation by reducing the production of IL-1β and IL-17 in bronchoalveolar lavage fluid as well as the number of group 3 innate lymphoid cells (ILC3s) in lung tissues. To clarify the functional mechanism of MlEVs in NA, the effect of MlEVs on airway epithelial cells (AECs) and immune cells was investigated ex vivo. According to microarray analysis, MlEVs upregulated hsa-miR-4517 expression in AECs. Moreover, this miRNA could suppress IL-1β production by monocytes, resulting in the inhibition of ILC3 activation and neutrophil recruitment. These findings suggest that MlEVs could be a novel therapeutic agent for managing unresolved NA by regulating miRNA expression in AECs.
细菌胞外小泡（EV）已被证明可以调节各种肺部疾病，但其在哮喘中的作用仍不确定。为了证明黄体微球菌衍生EVs（MlEV）在哮喘中的临床意义，我们招募了45名哮喘患者（20名中性粒细胞性哮喘[NA]患者，25名嗜酸性粒细胞哮喘[EA]患者）和40名健康对照（HC）。当通过ELISA评估血清中MlEV特异性IgG1和IgG4的患病率时，哮喘患者中的MlEV特异性IgG4（而非IgG1）水平低于HC。在哮喘患者中，NA患者的MIEV特异性IgG4水平显著低于EA患者。此外，血清MlEV特异性IgG4水平与FEV1（%）值呈正相关。在哮喘C57BL/6小鼠中，MlEVs通过减少支气管肺泡灌洗液中IL-1β和IL-17的产生以及肺组织中第3组固有淋巴细胞（ILC3s）的数量，显著减轻中性粒细胞气道炎症。为了阐明MlEVs在NA中的功能机制，体外研究了MlEVs对气道上皮细胞（AECs）和免疫细胞的影响。根据微阵列分析，MlEV上调了AECs中hsa-miR-4517的表达。此外，这种miRNA可以抑制单核细胞产生IL-1β，从而抑制ILC3的活化和中性粒细胞的募集。这些发现表明，MlEVs可能是一种新的治疗剂，通过调节AECs中miRNA的表达来管理未解决的NA。
(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)
(Exp Mol Med. 2023 Jan 13. doi: 10.1038/s12276-022-00910-0.)
(Exp Mol Med. 2023 Jan 13. doi: 10.1038/s12276-022-00910-0.)
Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells
Soyoon Sim, Dong-Hyun Lee, Kwang-Sun Kim, Hyeon Ju Park, Yoon-Keun Kim, Youngwoo Choi, Hae-Sim Park
Abstract
Bacterial extracellular vesicles (EVs) have been shown to regulate various pulmonary diseases, but their functions in asthma remain uncertain. To demonstrate the clinical significance of Micrococcus luteus-derived EVs (MlEVs) in asthma, we enrolled 45 asthmatic patients (20 patients with neutrophilic asthma [NA], 25 patients with eosinophilic asthma [EA]) and 40 healthy controls (HCs). When the prevalence of IgG1 and IgG4 specific to MlEVs was evaluated in serum by ELISA, lower levels of MlEV-specific IgG4 (but not IgG1) were noted in asthmatic patients than in HCs. Among asthmatic patients, significantly lower levels of MIEV-specific IgG4 were noted in patients with NA than in those with EA. Moreover, there was a positive correlation between serum MlEV-specific IgG4 levels and FEV1 (%) values. In asthmatic C57BL/6 mice, MlEVs significantly attenuated neutrophilic airway inflammation by reducing the production of IL-1β and IL-17 in bronchoalveolar lavage fluid as well as the number of group 3 innate lymphoid cells (ILC3s) in lung tissues. To clarify the functional mechanism of MlEVs in NA, the effect of MlEVs on airway epithelial cells (AECs) and immune cells was investigated ex vivo. According to microarray analysis, MlEVs upregulated hsa-miR-4517 expression in AECs. Moreover, this miRNA could suppress IL-1β production by monocytes, resulting in the inhibition of ILC3 activation and neutrophil recruitment. These findings suggest that MlEVs could be a novel therapeutic agent for managing unresolved NA by regulating miRNA expression in AECs.
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肥胖和肥胖性哮喘的外周气道功能障碍
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