补体C5在重度哮喘嗜酸性粒细胞炎症中的作用
2025/08/18
摘要
背景及目的：已有证据表明补体系统在哮喘中被激活，但其在重度哮喘中的具体作用机制仍不明确。作者旨在通过分析痰蛋白组学，探讨补体系统（特别是补体C5）在重度哮喘中的作用。
方法：采用数据依赖性采集质谱技术（DDA-MS）分析了健康对照组和重度哮喘患者的痰蛋白质组学表达谱。采用加权基因共表达网络分析（WGCNA）来定义与临床、生理学和炎症特征高度相关的独特模块。针对补体C5通路蛋白水平及受C5影响的嗜酸性粒细胞蛋白表达进行差异分析，并利用哮喘小鼠模型验证C5的促炎作用及其抑制效果。
结果：WGCNA分析显示，与补体系统激活相关的"棕色模块"与嗜酸性粒细胞炎症呈显著正相关。具体而言，痰嗜酸粒细胞≥3%的患者中，C5及其下游补体蛋白表达水平显著高于低嗜酸粒细胞组（<3%）。C5表达降低的患者表现出更轻的嗜酸粒细胞炎症和更好的肺功能。单细胞RNA测序与免疫荧光染色证实，巨噬细胞是C5的主要来源。体内实验表明，抑制C5可减轻过敏小鼠模型的炎症反应，而在IL-5转基因小鼠中直接给予重组C5则会加剧嗜酸粒细胞炎症。
结论：本研究首次明确C5通过巨噬细胞来源途径直接加重重度哮喘的嗜酸粒细胞性炎症，为靶向补体系统的精准治疗提供了理论依据。
关键词：C5aR1；C5aR2；补体C5；补体C5受体；嗜酸性粒细胞炎症；重度哮喘；加权基因共表达网络分析。
Abstract
Background: We investigated the role of the complement system, particularly complement C5, in severe asthma defined from an analysis of sputum proteomics. Although there has been evidence of complement activation in asthma, its role in severe asthma remains unclear.
Method: Sputum protein expression profiles were analyzed from healthy controls and severe asthma patients using data-dependent acquisition mass spectrometry. Weighted correlation network analysis (WGCNA) was used to define the unique modules that were highly correlated with clinical, physiologic, and inflammatory traits. Differential analysis was performed for the complement C5 pathway protein levels and eosinophilic protein expression as influenced by C5. Asthmatic mouse models were used to verify the effect of complement C5 administration and inhibition.
Results: The WGCNA "brown" module related to the complement system activation was positively correlated with eosinophilic inflammation. Specifically, C5 and downstream complement proteins were up-regulated in patients with high sputum eosinophil levels (≥ 3%) compared to low sputum eosinophils (< 3%). Patients with reduced C5 expression had less eosinophilic inflammation and better lung function. Using single-cell RNA sequencing and immunofluorescence staining led to identification of macrophages as the main source of C5. In vivo experiments confirmed that inhibiting C5 reduced inflammation in allergic mouse models, while direct stimulation with recombinant C5 in IL-5 transgenic mice increased eosinophilic inflammation.
Conclusion: We demonstrate a direct role for complement C5 in exacerbating eosinophilic inflammation in severe asthma.
Keywords: C5aR1; C5aR2; complement C5; complement C5 receptors; eosinophilic inflammation; severe asthma; weighted correlation network analysis.
背景及目的：已有证据表明补体系统在哮喘中被激活，但其在重度哮喘中的具体作用机制仍不明确。作者旨在通过分析痰蛋白组学，探讨补体系统（特别是补体C5）在重度哮喘中的作用。
方法：采用数据依赖性采集质谱技术（DDA-MS）分析了健康对照组和重度哮喘患者的痰蛋白质组学表达谱。采用加权基因共表达网络分析（WGCNA）来定义与临床、生理学和炎症特征高度相关的独特模块。针对补体C5通路蛋白水平及受C5影响的嗜酸性粒细胞蛋白表达进行差异分析，并利用哮喘小鼠模型验证C5的促炎作用及其抑制效果。
结果：WGCNA分析显示，与补体系统激活相关的"棕色模块"与嗜酸性粒细胞炎症呈显著正相关。具体而言，痰嗜酸粒细胞≥3%的患者中，C5及其下游补体蛋白表达水平显著高于低嗜酸粒细胞组（<3%）。C5表达降低的患者表现出更轻的嗜酸粒细胞炎症和更好的肺功能。单细胞RNA测序与免疫荧光染色证实，巨噬细胞是C5的主要来源。体内实验表明，抑制C5可减轻过敏小鼠模型的炎症反应，而在IL-5转基因小鼠中直接给予重组C5则会加剧嗜酸粒细胞炎症。
结论：本研究首次明确C5通过巨噬细胞来源途径直接加重重度哮喘的嗜酸粒细胞性炎症，为靶向补体系统的精准治疗提供了理论依据。
关键词：C5aR1；C5aR2；补体C5；补体C5受体；嗜酸性粒细胞炎症；重度哮喘；加权基因共表达网络分析。
（南方医科大学南方医院 樊可可 朱邦 赵文驱 赵海金）
（Dong C, Lu S, et, al.. Role for Complement C5 in Eosinophilic Inflammation of Severe Asthma. Allergy. 2025 Jun 16. doi: 10.1111/all.16616. Epub ahead of print. PMID: 40524528.）
Abstract
Background: We investigated the role of the complement system, particularly complement C5, in severe asthma defined from an analysis of sputum proteomics. Although there has been evidence of complement activation in asthma, its role in severe asthma remains unclear.
Method: Sputum protein expression profiles were analyzed from healthy controls and severe asthma patients using data-dependent acquisition mass spectrometry. Weighted correlation network analysis (WGCNA) was used to define the unique modules that were highly correlated with clinical, physiologic, and inflammatory traits. Differential analysis was performed for the complement C5 pathway protein levels and eosinophilic protein expression as influenced by C5. Asthmatic mouse models were used to verify the effect of complement C5 administration and inhibition.
Results: The WGCNA "brown" module related to the complement system activation was positively correlated with eosinophilic inflammation. Specifically, C5 and downstream complement proteins were up-regulated in patients with high sputum eosinophil levels (≥ 3%) compared to low sputum eosinophils (< 3%). Patients with reduced C5 expression had less eosinophilic inflammation and better lung function. Using single-cell RNA sequencing and immunofluorescence staining led to identification of macrophages as the main source of C5. In vivo experiments confirmed that inhibiting C5 reduced inflammation in allergic mouse models, while direct stimulation with recombinant C5 in IL-5 transgenic mice increased eosinophilic inflammation.
Conclusion: We demonstrate a direct role for complement C5 in exacerbating eosinophilic inflammation in severe asthma.
Keywords: C5aR1; C5aR2; complement C5; complement C5 receptors; eosinophilic inflammation; severe asthma; weighted correlation network analysis.
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阻断迷走神经TRPA1-肺神经内分泌细胞信号通路可缓解哮喘严重程度
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