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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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
Volume140
Issue number6
DOIs
StatePublished - Dec 1 2017

Fingerprint

STAT6 Transcription Factor
Transcription Factor CHOP
Interleukin-4 Receptors
Endoplasmic Reticulum Stress
Interleukin-4
Transcription Factors
Asthma
Macrophages
Ovalbumin
Inflammation
Protein Deficiency
Airway Remodeling

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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

In: Journal of Allergy and Clinical Immunology, Vol. 140, No. 6, 01.12.2017, p. 1550-1561.e8.

Research output: Contribution to journalArticle

Wang, Yi ; Zhu, Jianghui ; Zhang, Lei ; Zhang, Zhijun ; He, Long ; Mou, Yong ; Deng, Yanhan ; Cao, Yong ; Yang, Ping ; Su, Yunchao ; Zhao, Jianping ; Zhang, Shu ; Yu, Qilin ; Hu, Jifa ; Chen, Zhishui ; Ning, Qin ; Xiang, Xudong ; Xu, Yongjian ; Wang, Cong Yi ; Xiong, Weining. / 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. In: Journal of Allergy and Clinical Immunology. 2017 ; Vol. 140, No. 6. pp. 1550-1561.e8.
@article{e156bc6c320649b1a2880fa36f5d201e,
title = "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",
abstract = "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.",
keywords = "C/EBP homologous protein, asthma, endoplasmic reticulum stress, macrophage",
author = "Yi Wang and Jianghui Zhu and Lei Zhang and Zhijun Zhang and Long He and Yong Mou and Yanhan Deng and Yong Cao and Ping Yang and Yunchao Su and Jianping Zhao and Shu Zhang and Qilin Yu and Jifa Hu and Zhishui Chen and Qin Ning and Xudong Xiang and Yongjian Xu and Wang, {Cong Yi} and Weining Xiong",
year = "2017",
month = "12",
day = "1",
doi = "10.1016/j.jaci.2017.01.024",
language = "English (US)",
volume = "140",
pages = "1550--1561.e8",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "6",

}

TY - JOUR

T1 - 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

AU - Wang, Yi

AU - Zhu, Jianghui

AU - Zhang, Lei

AU - Zhang, Zhijun

AU - He, Long

AU - Mou, Yong

AU - Deng, Yanhan

AU - Cao, Yong

AU - Yang, Ping

AU - Su, Yunchao

AU - Zhao, Jianping

AU - Zhang, Shu

AU - Yu, Qilin

AU - Hu, Jifa

AU - Chen, Zhishui

AU - Ning, Qin

AU - Xiang, Xudong

AU - Xu, Yongjian

AU - Wang, Cong Yi

AU - Xiong, Weining

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - C/EBP homologous protein

KW - asthma

KW - endoplasmic reticulum stress

KW - macrophage

UR - http://www.scopus.com/inward/record.url?scp=85017384496&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017384496&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2017.01.024

DO - 10.1016/j.jaci.2017.01.024

M3 - Article

VL - 140

SP - 1550-1561.e8

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 6

ER -