Yi Wang1, Jianghui Zhu2, Lei Zhang1, Zhijun Zhang2, Long He2, Yong Mou1, Yanhan Deng1, Yong Cao1, Ping Yang2, Yunchao Su3, Jianping Zhao4, Shu Zhang2, Qilin Yu2, Jifa Hu5, Zhishui Chen6, Qin Ning7, Xudong Xiang8, Yongjian Xu1, Cong-Yi Wang9, Weining Xiong10. 1. 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. 2. Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China. 3. Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Ga. 4. 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. 5. Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. 6. 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. 7. Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China. 8. Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, Second Xiangya Hospital, Central South University, Changsha, China. 9. 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. 10. 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.
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.
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.
Authors: Emily M Nakada; Nirav R Bhakta; Bethany R Korwin-Mihavics; Amit Kumar; Nicolas Chamberlain; Sierra R Bruno; David G Chapman; Sidra M Hoffman; Nirav Daphtary; Minara Aliyeva; Charles G Irvin; Anne E Dixon; Prescott G Woodruff; Shantu Amin; Matthew E Poynter; Dhimant H Desai; Vikas Anathy Journal: JCI Insight Date: 2019-05-02
Authors: Yong Gyu Lee; Brenda F Reader; Derrick Herman; Adam Streicher; Joshua A Englert; Mathias Ziegler; Sangwoon Chung; Manjula Karpurapu; Gye Young Park; John W Christman; Megan N Ballinger Journal: JCI Insight Date: 2019-02-21