IL-22缺陷介导COPD急性加重嗜酸性粒细胞增多的机制研究

A growing body of evidence supports an association between sputum/blood eosinophilia and acute exacerbations of COPD (AECOPD). Importantly, eosinophilia may predict susceptibility to AECOPD. Previous studies found that IL-33/ type 2 innate lymphoid cells (ILC2) signal may play a significant role in eosinophilia in AECOPD. In vivo and in vitro studies showed that in the presence of chronic cigarette smoking (CS) exposure and pathogen respiratory infections, IL-22 production would be significantly suppressed, resulting in IL-22 defect. Considering the anti-inflammatory property of IL-22 in COPD, IL-22 defect causes restricted antimicrobial activity, delayed clearance of pathogen and greater airway inflammation, increasing the susceptibility to COPD exacerbations. We conjecture that IL-22 defect happens in events of AECOPD, which could induce eosinophilia through Reg3γ-dependent upregulation of IL-33/ILC2 signal. In this project, we will observe the correlation between IL-22 defect and eosinophilia in AECOPD patients through cross-sectional study. Besides, we will explore the molecular mechanism of IL-22 defect mediated eosinophilia in AECOPD mice models induced by chronic CS exposure and lipopolysaccharide intratracheal instillation by observing airway inflammation and production of Reg3γ and IL-33, as well as ILC2 proportion and activation, with Reg3γ antibody and/or recombinant IL-22. Our project aims to reveal the molecular association between IL-22 defect and eosinophilia in AECOPD, and uncover the underlying mechanism linking eosinophilia and susceptibility to AECOPD, providing evidence for the use of IL-22 targeted medication in the treatment of airway inflammation in AECOPD.

嗜酸性粒细胞增多与COPD急性加重（AECOPD）易感性相关。香烟暴露合并病原体感染抑制IL-22产生，形成IL-22缺陷。IL-22缺陷通过抑制病原体清除、加剧气道炎症介导AECOPD易感性。研究发现IL-33/2型固有淋巴细胞（ILC2）信号可能参与AECOPD嗜酸性粒细胞增多。我们推测AECOPD存在IL-22缺陷，通过抑制Reg3γ表达，上调IL-33/ILC2信号，介导嗜酸性粒细胞增多。本项目拟采用横断面研究探索IL-22缺陷与AECOPD患者嗜酸性粒细胞的相关性，香烟烟雾联合脂多糖建立AECOPD小鼠模型，Reg3γ抗体和/或IL-22气道干预，观察气道炎症、Reg3γ、IL-33水平及ILC2增殖活化，探讨IL-22缺陷介导AECOPD嗜酸性粒细胞增多的分子机制，揭示嗜酸性粒细胞增多预测AECOPD易感性的潜在机制，为IL-22作为AECOPD气道炎症治疗靶点提供依据。

背景：COPD急性加重（acute exacerbations of COPD，AECOPD）是COPD病死率增加的主要原因。近年研究发现，嗜酸性粒细胞与AECOPD风险密切相关。IL-22可能通过上调Reg3γ表达，抑制IL-33/ILC2信号，抑制嗜酸性粒细胞性气道炎症。.研究目的：探索IL-22与AECOPD嗜酸性粒细胞的相关性及其分子机制。.研究内容：（1）通过横断面研究，纳入COPD稳定期患者（stable COPD，sCOPD）105人，分为非吸烟sCOPD、吸烟sCOPD、非吸烟AECOPD和吸烟AECOPD四组。比较各组外周血嗜酸性粒细胞、IL-22、IL-33水平、ILC2增值及活性，初步了解IL-22与AECOPD嗜酸性粒细胞数之间的相关性；（2）将C57BL/6小鼠随机分为Control组、LPS组、CS组及CS+LPS组，采用香烟烟雾（CS）吸入联合脂多糖（LPS）气道注入法，建立AECOPD小鼠模型，对比各组小鼠肺组织病理改变，嗜酸性粒细胞数，IL-22、IL-33、Reg3γ水平，肺组织ILC2增值及活性；（3）将C57BL/6小鼠随机分为CS+LPS组，IL-22组，IL-22+anti-Reg3γ组，对比各组小鼠肺组织病理改变，肺泡灌洗液嗜酸性粒细胞数、IL-33水平、肺组织匀浆ILC2增值及活性。.研究结果及关键数据：（1）AECOPD患者IL-22水平升高，嗜酸性粒细胞及IL-33水平降低，外周血ILC2增值及活性降低；IL-22水平与嗜酸性粒细胞及IL-33水平呈负相关，与ILC2增殖及活性均呈负相关。（2）AECOPD小鼠IL-22升高，嗜酸性粒细胞水平降低，IL-33水平下降，肺组织ILC2活性及比例降低，肺组织Reg3γ水平显著升高；IL-22与IL-33呈负相关，与Reg3γ呈正相关；IL-22可抑制小鼠IL-33、嗜酸性粒细胞数以及ILC2增殖及活化，anti-Reg3γ可减弱IL-22的抑制作用。.研究结论：IL-22可能通过Reg3γ依赖途径抑制IL-33/ILC2信号通路，介导急性加重COPD嗜酸性粒细胞降低。.研究意义：本研究揭示了AECOPD过程中嗜酸性粒细胞降低的部分分子机制，为IL-22作为预测AECOPD的生物标志物及气道炎症治疗的新靶点提供依据。