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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:140

Article

Wang, Yi^1,2  Zhu, Jianghui¹  Zhang, Lei^1,2  Zhang, Zhijun¹  He, Long¹  Mou, Yong^1,2  Deng, Yanhan^1,2  Cao, Yong^1,2  Yang, Ping¹  Su, Yunchao³  Zhao, Jianping²  Zhang, Shu¹  Yu, Qilin¹  Hu, Jifa⁴  Chen, Zhishui^1,4  Ning, Qin⁵  Xiang, Xudong⁶  Xu, Yongjian^1,2  Wang, Cong-Yi^1,4  Xiong, Weining^1,2 

[1] Minist Hlth, Key Lab Organ Transplantat, Minist Educ, Ctr Biomed Res, Wuhan, Hubei, Peoples R China

[2] Huazhong Univ Sci & Technol, Dept Resp & Crit Care Med, Key Lab Pulm Dis,Hlth Minist,Tongji Med Coll, Key Cite Natl Clin Res Ctr Resp Dis,Tongji Hosp, Wuhan, Hubei, Peoples R China

[3] Georgia Regents Univ, Med Coll Georgia, Dept Pharmacol & Toxicol, Augusta, GA USA

[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Sponsored Program Adm, Wuhan, Hubei, Peoples R China

[5] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Infect Dis, Wuhan, Hubei, Peoples R China

[6] Cent S Univ, Dept Emergency Med, Xiangya Hosp 2, Inst Emergency Med & Rare Dis, Changsha, Hunan, Peoples R China

关键词: C/EBP homologous protein;    asthma;    macrophage;    endoplasmic reticulum stress;   

DOI  :  10.1016/j.jaci.2017.01.024

来源: Elsevier

【 摘 要 】

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 2/2 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 a 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 a 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.

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