纤维胶凝蛋白A通过抑制ILC2驱动的2型炎症来预防过敏性哮喘
2025/08/01
摘要
背景：2型炎症是哮喘的关键机制，涉及先天和适应性免疫。人纤维胶凝素(FCN)-2 （L-ficolin, P35）及其小鼠同源物FCN- A是血浆/血清中主要的模式识别分子之一，是凝集素补体系统的重要启动子，在包括呼吸系统免疫在内的免疫中发挥重要作用。然而，目前对FCN-2/A在过敏性哮喘中的作用知之甚少。
方法：采用ELISA法检测90例过敏性哮喘患者和48例健康对照者血清FCN-2和IgE水平。在野生型（WT）和FCN-A敲除（KO）小鼠中建立吸入变应原屋尘螨（HDM）诱导的哮喘小鼠模型。采用FCM、RT-qPCR、Western blot和ELISA检测小鼠血清和支气管肺泡灌洗液（BALF） IgE水平、肺固有淋巴样细胞（ILC）1/2/3、转录因子GATA3、T-bet和RORγt的表达以及血清和BALF中2型细胞因子的浓度。
结果：过敏性哮喘患者血清FCN-2浓度显著低于健康对照组。同样，hdm诱导的哮喘小鼠血清和BALF中FCN-A浓度低于未诱导的小鼠。在哮喘小鼠模型中，与野生型哮喘小鼠相比，FCN-A KO哮喘小鼠的总IgE和hdm特异性IgE （sIgE）、β-己糖胺酶（β-HEX）和组胺分泌水平升高，气道上皮通透性增加，血清中fitc -右旋糖酐释放，炎症细胞浸润和嗜酸性粒细胞计数增加，疾病症状和组织学损伤更严重。FCN-A KO哮喘小鼠T-bet+ ILC1比例降低，IL-5+/IL-13+ ILC2/ILC2比例升高，p-GATA3表达增加，血清和BALF中2型细胞因子IL-4、IL-5和IL-13， Th17细胞因子IL-17和趋化因子CCL2/4产生增加。重要的是，外源性FCN-A通过降低ILC2比例和2型细胞因子的表达，以及血清总IgE和过敏原特异性IgE的产生来保护小鼠的过敏性气道炎症。这些结果表明，在哮喘期间，FCN-A抑制ILC2固有免疫和ige介导的适应性免疫。
结论：我们的研究结果提供了以前未报道的证据，表明FCN-A通过抑制肺ILC2驱动的2型炎症来预防过敏性哮喘。
Ficolin-A Protects Against Allergic Asthma via Suppressing ILC2-Drived Type 2 Inflammation
Yu-Ke Xie, Shan-Shan Xu, Yong-Shuai Li, Jiarong Li, Shu-Chen Zhang, Yan Xie, Ya-Dong Gao, Xiao-Lian Zhang
Abstract
Background: Type 2 inflammation has emerged as a pivotal mechanism for asthma, which involves both innate and adaptive immunity. Human ficolin (FCN)-2 (L-ficolin, P35) and its mouse homolog FCN-A are one of the major pattern recognition molecules of plasma/serum, acting as important initiators of the lectin complement system and playing important roles in immunity, including respiratory immunity. However, little is known about the role of FCN-2/A in allergic asthma.
Methods: Serum FCN-2 and IgE levels in 90 allergic asthmatic patients and 48 healthy controls were measured by ELISA. Aeroallergen house dust mite (HDM)-induced mouse model of asthma was generated in both wild type (WT) and FCN-A knockout (KO) mice. Mouse serum and bronchoalveolar lavage fluid (BALF) IgE levels, lung innate lymphoid cells (ILC)1/2/3, the expression of transcription factors GATA3, T-bet, and RORγt, and the concentrations of type 2 cytokines in serum and BALF were measured by FCM, RT-qPCR, Western blot, and ELISA.
Results: Serum FCN-2 concentrations in patients with allergic asthma were significantly lower than those in healthy controls. Similarly, lower serum and BALF FCN-A concentrations were observed in HDM-induced asthma mouse models compared to those of uninduced mice. In the asthma mouse model, FCN-A KO asthmatic mice had higher levels of total IgE and HDM-specific IgE (sIgE), β-hexosaminidase (β-HEX) and histamine secretion, as well as increased airway epithelial permeability with the release of FITC-dextran in sera, inflammatory cell infiltration and eosinophil counts, and displayed more severe disease symptoms with histological damage compared to WT asthmatic mice. FCN-A KO asthmatic mice showed decreased T-bet+ ILC1 and increased IL-5+/IL-13+ ILC2/ILC2 proportions, p-GATA3 expression, serum and BALF type 2 cytokines IL-4, IL-5, and IL-13, Th17 cytokine IL-17, and chemokines CCL2/4 production. Importantly, the administration of exogenous FCN-A protected against mouse allergic airway inflammation with decreased ILC2 proportions and type 2 cytokines expression, serum total and allergen-specific IgE production. These results suggest that FCN-A suppresses both ILC2 innate immunity and IgE-mediated adaptive immunity during asthma.
Conclusion: Our findings provide previously unreported evidence that FCN-A protects against allergic asthma by suppressing lung ILC2-driven type 2 inflammation.
背景：2型炎症是哮喘的关键机制，涉及先天和适应性免疫。人纤维胶凝素(FCN)-2 （L-ficolin, P35）及其小鼠同源物FCN- A是血浆/血清中主要的模式识别分子之一，是凝集素补体系统的重要启动子，在包括呼吸系统免疫在内的免疫中发挥重要作用。然而，目前对FCN-2/A在过敏性哮喘中的作用知之甚少。
方法：采用ELISA法检测90例过敏性哮喘患者和48例健康对照者血清FCN-2和IgE水平。在野生型（WT）和FCN-A敲除（KO）小鼠中建立吸入变应原屋尘螨（HDM）诱导的哮喘小鼠模型。采用FCM、RT-qPCR、Western blot和ELISA检测小鼠血清和支气管肺泡灌洗液（BALF） IgE水平、肺固有淋巴样细胞（ILC）1/2/3、转录因子GATA3、T-bet和RORγt的表达以及血清和BALF中2型细胞因子的浓度。
结果：过敏性哮喘患者血清FCN-2浓度显著低于健康对照组。同样，hdm诱导的哮喘小鼠血清和BALF中FCN-A浓度低于未诱导的小鼠。在哮喘小鼠模型中，与野生型哮喘小鼠相比，FCN-A KO哮喘小鼠的总IgE和hdm特异性IgE （sIgE）、β-己糖胺酶（β-HEX）和组胺分泌水平升高，气道上皮通透性增加，血清中fitc -右旋糖酐释放，炎症细胞浸润和嗜酸性粒细胞计数增加，疾病症状和组织学损伤更严重。FCN-A KO哮喘小鼠T-bet+ ILC1比例降低，IL-5+/IL-13+ ILC2/ILC2比例升高，p-GATA3表达增加，血清和BALF中2型细胞因子IL-4、IL-5和IL-13， Th17细胞因子IL-17和趋化因子CCL2/4产生增加。重要的是，外源性FCN-A通过降低ILC2比例和2型细胞因子的表达，以及血清总IgE和过敏原特异性IgE的产生来保护小鼠的过敏性气道炎症。这些结果表明，在哮喘期间，FCN-A抑制ILC2固有免疫和ige介导的适应性免疫。
结论：我们的研究结果提供了以前未报道的证据，表明FCN-A通过抑制肺ILC2驱动的2型炎症来预防过敏性哮喘。
（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）
（Allergy. 2025 Jul 25. doi: 10.1111/all.16661.）
Ficolin-A Protects Against Allergic Asthma via Suppressing ILC2-Drived Type 2 Inflammation
Yu-Ke Xie, Shan-Shan Xu, Yong-Shuai Li, Jiarong Li, Shu-Chen Zhang, Yan Xie, Ya-Dong Gao, Xiao-Lian Zhang
Abstract
Background: Type 2 inflammation has emerged as a pivotal mechanism for asthma, which involves both innate and adaptive immunity. Human ficolin (FCN)-2 (L-ficolin, P35) and its mouse homolog FCN-A are one of the major pattern recognition molecules of plasma/serum, acting as important initiators of the lectin complement system and playing important roles in immunity, including respiratory immunity. However, little is known about the role of FCN-2/A in allergic asthma.
Methods: Serum FCN-2 and IgE levels in 90 allergic asthmatic patients and 48 healthy controls were measured by ELISA. Aeroallergen house dust mite (HDM)-induced mouse model of asthma was generated in both wild type (WT) and FCN-A knockout (KO) mice. Mouse serum and bronchoalveolar lavage fluid (BALF) IgE levels, lung innate lymphoid cells (ILC)1/2/3, the expression of transcription factors GATA3, T-bet, and RORγt, and the concentrations of type 2 cytokines in serum and BALF were measured by FCM, RT-qPCR, Western blot, and ELISA.
Results: Serum FCN-2 concentrations in patients with allergic asthma were significantly lower than those in healthy controls. Similarly, lower serum and BALF FCN-A concentrations were observed in HDM-induced asthma mouse models compared to those of uninduced mice. In the asthma mouse model, FCN-A KO asthmatic mice had higher levels of total IgE and HDM-specific IgE (sIgE), β-hexosaminidase (β-HEX) and histamine secretion, as well as increased airway epithelial permeability with the release of FITC-dextran in sera, inflammatory cell infiltration and eosinophil counts, and displayed more severe disease symptoms with histological damage compared to WT asthmatic mice. FCN-A KO asthmatic mice showed decreased T-bet+ ILC1 and increased IL-5+/IL-13+ ILC2/ILC2 proportions, p-GATA3 expression, serum and BALF type 2 cytokines IL-4, IL-5, and IL-13, Th17 cytokine IL-17, and chemokines CCL2/4 production. Importantly, the administration of exogenous FCN-A protected against mouse allergic airway inflammation with decreased ILC2 proportions and type 2 cytokines expression, serum total and allergen-specific IgE production. These results suggest that FCN-A suppresses both ILC2 innate immunity and IgE-mediated adaptive immunity during asthma.
Conclusion: Our findings provide previously unreported evidence that FCN-A protects against allergic asthma by suppressing lung ILC2-driven type 2 inflammation.
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小鼠Th2细胞外泌体通过表面细胞因子IL-3促进嗜酸性粒细胞存活
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生物钟紊乱和非2型哮喘：免疫、上皮和类固醇反应的假说驱动视角
