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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Long
authors.initials: L
authors.lastname: He
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Mou
authors.affiliation: 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.
authors.forename: Yanhan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Ga.
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Jifa
authors.initials: J
authors.lastname: Hu
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China; Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Zhishui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China; Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. Electronic address: wangcy@tjh.tjmu.edu.cn.
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
authors.affiliation: 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. Electronic address: xiongweining@tjh.tjmu.edu.cn.
authors.forename: Weining
authors.initials: W
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000276:immunology*; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; D051742:Transcription Factor CHOP; C530718:CEBPA protein, mouse; C497250:Ddit3 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse; C484069:Tcfec protein, mouse
keywords: C/EBP homologous protein; asthma; endoplasmic reticulum stress; macrophage