Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor α positive feedback loop in M2 macrophages

Yi Wang, Jianghui Zhu, Lei Zhang, Zhijun Zhang, Long He, Yong Mou, Yanhan Deng, Yong Cao, Ping Yang, Yunchao Su, Jianping Zhao, Shu Zhang, Qilin Yu, Jifa Hu, Zhishui Chen, Qin Ning, Xudong Xiang, Yongjian Xu, Cong Yi Wang, Weining Xiong

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18 Scopus citations


Background 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. Objectives We aimed to determine the function and mechanism of Chop in the pathogenesis of allergic asthma in patients and animals. Methods 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. Results 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. Conclusions Chop and ER stress are implicated in asthma pathogenesis, which involves regulation of M2 programming in macrophages.

Original languageEnglish (US)
Pages (from-to)1550-1561.e8
JournalJournal of Allergy and Clinical Immunology
Issue number6
Publication statusPublished - Dec 2017



  • C/EBP homologous protein
  • asthma
  • endoplasmic reticulum stress
  • macrophage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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