EcN-Sj16-Exo 通过上调 N-WASP 抑制嗜酸性粒细胞胞外陷阱形成，从而改善实验性哮喘
2026/03/05
摘要
背景：嗜酸性粒细胞性炎症是过敏性哮喘的特征之一，耗竭嗜酸性粒细胞已被证实可缓解症状。支气管肺泡灌洗液（BALF）中嗜酸性粒细胞胞外陷阱（EETs）水平升高与哮喘严重程度相关。Sj16是一种源自日本血吸虫的蛋白，具有已知的免疫调节特性。外泌体因其具有保护性的磷脂双分子层，可作为高效的药物载体。
方法：我们提取了经改造表达 Sj16的Nissle1917 大肠杆菌（EcN-Sj16）所分泌的外泌体（EcN-Sj16-Exo），并旨在研究 EcN-Sj16-Exo 在哮喘中的作用。在卵清蛋白（OVA）诱导的小鼠实验性哮喘模型中，EET 水平升高。我们使用 EcN-Sj16-Exo 对实验性哮喘模型进行治疗。通过免疫荧光和扫描电子显微镜评估 EET 的形成。评估肺功能、气道重塑和炎症情况。使用Wiskott-Aldrich 综合征样蛋白（WASL）基因敲除小鼠和表达神经型 Wiskott-Aldrich 综合征蛋白（N-WASP）的重组腺相关病毒（rAAV）来探讨 EcN-Sj16-Exo 的潜在作用机制。
结果：哮喘患者痰液和BALF中EET形成增加。我们证实，Sj16在体外可抑制EET形成，并且当由 EcN-Sj16 分泌时，其主要定位于外泌体中。在实验性哮喘模型中，EcN-Sj16-Exo 显著减少了 EET 的形成。此外，EcN-Sj16-Exo 显著减轻了气道高反应性（AHR）和气道重塑，表现为肺阻力（R（L））降低、动态顺应性（C（dyn））改善，以及炎症细胞浸润、纤维化和黏液高分泌减少。进一步地，EcN-Sj16-Exo 降低了 BALF 中嗜酸性粒细胞和中性粒细胞计数、IgE及2型细胞因子水平，同时增加了脾脏中的调节性T细胞（Treg）。在机制上，EcN-Sj16-Exo 通过上调N-WASP来抑制EET形成。WASL基因敲除小鼠以及 AAV6-WASL介导的N-WASP表达实验证实，EcN-Sj16-Exo通过上调N-WASP抑制 EET 形成，从而减轻实验性哮喘。
结论：我们的研究结果表明，EcN-Sj16-Exo 代表了一种有前景的哮喘治疗方法，并突出了在哮喘治疗中靶向 EETs 和 N-WASP 的潜力。
EcN-Sj16-Exo ameliorates experimental asthma by inhibiting eosinophil extracellular traps formation via N-WASP upregulation.
Xi, Sun; Yao, Liao; Ji, Wu;
Abstrast
BACKGROUND: Eosinophilic inflammation is a feature of allergic asthma, with eosinophil depletion shown to alleviate symptoms. Elevated levels of eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid (BALF) correlate with asthma severity. Sj16 is a protein from Schistosoma japonicum with known immunoregulatory properties. Exosomes, with their protective phospholipid bilayer, serve as efficient drug carriers.
METHODS: We extracted exosomes secreted by Escherichia coli Nissle 1917 engineered to express Sj16 (EcN-Sj16-Exo), and sought to investigate the role of EcN-Sj16-Exo on asthma. In ovalbumin (OVA)-induced experimental asthma model in mice, EET levels were elevated. The experimental asthma model was treated with EcN-Sj16-Exo. EET formation was assessed using immunofluorescence and scanning electron microscopy. Lung function, airway remodeling, and inflammatory were evaluated. Wiskott-Aldrich syndrome-like (WASL) knockout mice and recombinant adeno-associated virus (rAAV)-expressing Neural Wiskott-Aldrich syndrome protein (N-WASP) were used to investigate the potential mechanisms of EcN-Sj16-Exo.
RESULTS: EET formation was increased in sputum and BALF from asthma patients. We demonstrate that Sj16 inhibits EET formation in vitro and localizes primarily in exosomes when secreted by EcN-Sj16. In the experimental asthma model, EcN-Sj16-Exo significantly reduced EET formation. Moreover, EcN-Sj16-Exo significantly attenuated airway hyperreactivity (AHR) and airway remodeling, as evidenced by reduced lung resistance (R(L)), improved dynamic compliance (C(dyn)), and diminished inflammatory cell infiltration, fibrosis, and mucus hypersecretion. Furthermore, EcN-Sj16-Exo decreased eosinophil and neutrophil counts, IgE, and type 2 cytokines levels in BALF while increasing Treg cells in the spleen. Mechanistically, EcN-Sj16-Exo inhibited EET formation by upregulating N-WASP. WASL knockout mice and AAV6-WASL-mediated N-WASP expression confirmed that EcN-Sj16-Exo alleviates experimental asthma by upregulating N-WASP to inhibit EET formation.
CONCLUSION: Our findings suggest that EcN-Sj16-Exo represents a promising therapeutic approach in asthma, highlighting the potential of targeting EETs and N-WASP in asthma therapy.
背景：嗜酸性粒细胞性炎症是过敏性哮喘的特征之一，耗竭嗜酸性粒细胞已被证实可缓解症状。支气管肺泡灌洗液（BALF）中嗜酸性粒细胞胞外陷阱（EETs）水平升高与哮喘严重程度相关。Sj16是一种源自日本血吸虫的蛋白，具有已知的免疫调节特性。外泌体因其具有保护性的磷脂双分子层，可作为高效的药物载体。
方法：我们提取了经改造表达 Sj16的Nissle1917 大肠杆菌（EcN-Sj16）所分泌的外泌体（EcN-Sj16-Exo），并旨在研究 EcN-Sj16-Exo 在哮喘中的作用。在卵清蛋白（OVA）诱导的小鼠实验性哮喘模型中，EET 水平升高。我们使用 EcN-Sj16-Exo 对实验性哮喘模型进行治疗。通过免疫荧光和扫描电子显微镜评估 EET 的形成。评估肺功能、气道重塑和炎症情况。使用Wiskott-Aldrich 综合征样蛋白（WASL）基因敲除小鼠和表达神经型 Wiskott-Aldrich 综合征蛋白（N-WASP）的重组腺相关病毒（rAAV）来探讨 EcN-Sj16-Exo 的潜在作用机制。
结果：哮喘患者痰液和BALF中EET形成增加。我们证实，Sj16在体外可抑制EET形成，并且当由 EcN-Sj16 分泌时，其主要定位于外泌体中。在实验性哮喘模型中，EcN-Sj16-Exo 显著减少了 EET 的形成。此外，EcN-Sj16-Exo 显著减轻了气道高反应性（AHR）和气道重塑，表现为肺阻力（R（L））降低、动态顺应性（C（dyn））改善，以及炎症细胞浸润、纤维化和黏液高分泌减少。进一步地，EcN-Sj16-Exo 降低了 BALF 中嗜酸性粒细胞和中性粒细胞计数、IgE及2型细胞因子水平，同时增加了脾脏中的调节性T细胞（Treg）。在机制上，EcN-Sj16-Exo 通过上调N-WASP来抑制EET形成。WASL基因敲除小鼠以及 AAV6-WASL介导的N-WASP表达实验证实，EcN-Sj16-Exo通过上调N-WASP抑制 EET 形成，从而减轻实验性哮喘。
结论：我们的研究结果表明，EcN-Sj16-Exo 代表了一种有前景的哮喘治疗方法，并突出了在哮喘治疗中靶向 EETs 和 N-WASP 的潜力。
（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）
（Eur Respir J 2026 Feb 19;(0). DOI：10.1183/13993003.00948-2025 IF: 12.339）
（Eur Respir J 2026 Feb 19;(0). DOI：10.1183/13993003.00948-2025 IF: 12.339）
EcN-Sj16-Exo ameliorates experimental asthma by inhibiting eosinophil extracellular traps formation via N-WASP upregulation.
Xi, Sun; Yao, Liao; Ji, Wu;
Abstrast
BACKGROUND: Eosinophilic inflammation is a feature of allergic asthma, with eosinophil depletion shown to alleviate symptoms. Elevated levels of eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid (BALF) correlate with asthma severity. Sj16 is a protein from Schistosoma japonicum with known immunoregulatory properties. Exosomes, with their protective phospholipid bilayer, serve as efficient drug carriers.
METHODS: We extracted exosomes secreted by Escherichia coli Nissle 1917 engineered to express Sj16 (EcN-Sj16-Exo), and sought to investigate the role of EcN-Sj16-Exo on asthma. In ovalbumin (OVA)-induced experimental asthma model in mice, EET levels were elevated. The experimental asthma model was treated with EcN-Sj16-Exo. EET formation was assessed using immunofluorescence and scanning electron microscopy. Lung function, airway remodeling, and inflammatory were evaluated. Wiskott-Aldrich syndrome-like (WASL) knockout mice and recombinant adeno-associated virus (rAAV)-expressing Neural Wiskott-Aldrich syndrome protein (N-WASP) were used to investigate the potential mechanisms of EcN-Sj16-Exo.
RESULTS: EET formation was increased in sputum and BALF from asthma patients. We demonstrate that Sj16 inhibits EET formation in vitro and localizes primarily in exosomes when secreted by EcN-Sj16. In the experimental asthma model, EcN-Sj16-Exo significantly reduced EET formation. Moreover, EcN-Sj16-Exo significantly attenuated airway hyperreactivity (AHR) and airway remodeling, as evidenced by reduced lung resistance (R(L)), improved dynamic compliance (C(dyn)), and diminished inflammatory cell infiltration, fibrosis, and mucus hypersecretion. Furthermore, EcN-Sj16-Exo decreased eosinophil and neutrophil counts, IgE, and type 2 cytokines levels in BALF while increasing Treg cells in the spleen. Mechanistically, EcN-Sj16-Exo inhibited EET formation by upregulating N-WASP. WASL knockout mice and AAV6-WASL-mediated N-WASP expression confirmed that EcN-Sj16-Exo alleviates experimental asthma by upregulating N-WASP to inhibit EET formation.
CONCLUSION: Our findings suggest that EcN-Sj16-Exo represents a promising therapeutic approach in asthma, highlighting the potential of targeting EETs and N-WASP in asthma therapy.
上一篇：
没有了
下一篇：
直接靶向STAT3的苍耳亭通过抑制TSLP释放和NK2细胞极化缓解过敏性气道炎症
