Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China; Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, China.
Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
J Allergy Clin Immunol. 2017 Dec;140(6):1550-1561.e8. doi: 10.1016/j.jaci.2017.01.024. Epub 2017 Feb 24.
C/EBP homologous protein (Chop), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during asthma development. However, its exact role in asthma pathogenesis is not fully understood.
We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals.
Studies were conducted in asthmatic patients and Chop mice to dissect the role of Chop and ER stress in asthma pathogenesis. An ovalbumin (OVA)-induced allergic airway inflammation model was used to address the effect of Chop deficiency on asthma development. Next, the effect of Chop deficiency on macrophage polarization and related signaling pathways was investigated to demonstrate the underlying mechanisms.
Asthmatic patients and mice after OVA induction exhibited aberrant Chop expression along with ER stress. Specifically, Chop was noted to be specifically overexpressed in macrophages, and mice deficient in Chop were protected from OVA-induced allergic airway inflammation, as manifested by attenuated airway inflammation, remodeling, and hyperresponsiveness. Chop was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an IL-4/signal transducer and activator of transcription 6/transcription factor EC (Tfec)/IL-4 receptor α positive feedback regulatory loop, in which IL-4 induces Chop expression, which then promotes signal transducer and activator of transcription 6 signaling to transcribe Tfec expression. Finally, Tfec transcribes IL-4 receptor α expression to promote M2 programming in macrophages.
Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.
C/EBP 同源蛋白（Chop）是内质网（ER）应激的标志物，在哮喘发展过程中表现出异常的表达模式。然而，其在哮喘发病机制中的确切作用尚不完全清楚。
我们旨在确定 Chop 在患者和动物过敏性哮喘发病机制中的功能和机制。
在哮喘患者和 Chop 小鼠中进行研究，以剖析 Chop 和 ER 应激在哮喘发病机制中的作用。使用卵清蛋白（OVA）诱导的过敏性气道炎症模型来解决 Chop 缺乏对哮喘发展的影响。接下来，研究 Chop 缺乏对巨噬细胞极化和相关信号通路的影响，以阐明潜在的机制。
OVA 诱导后的哮喘患者和小鼠表现出异常的 Chop 表达和 ER 应激。具体而言，Chop 在巨噬细胞中特异性过表达，而 Chop 缺乏的小鼠则免受 OVA 诱导的过敏性气道炎症的影响，表现为气道炎症、重塑和高反应性减轻。Chop 通过增强巨噬细胞中的 M2 编程加重过敏性气道炎症。机制研究描述了一个 IL-4/信号转导和转录激活因子 6/转录因子 EC（Tfec）/IL-4 受体α正反馈调节环，其中 IL-4 诱导 Chop 表达，然后促进信号转导和转录激活因子 6 信号转导转录 Tfec 表达。最后，Tfec 转录 IL-4 受体α表达以促进巨噬细胞中的 M2 编程。
Chop 和 ER 应激参与哮喘发病机制，涉及调节巨噬细胞中的 M2 编程。
