Role of C/EBP homologous protein (CHOP) and Endoplasmic Reticulum in Asthma Exacerbation by Regulating the IL-4/STAT6/Tfec/IL-4Rα Positive Feedback Loop in M2 Macrophages

Publication date: Available online 24 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundC/EBP homologous protein (CHOP), a marker of endoplasmic reticulum (ER) stress, exhibits aberrant expression patterns during the development of asthma. However, its exact role in asthma pathogenesis is not fully understood.ObjectivesWe aimed to determine the function and mechanism of CHOP in the pathogenesis of allergic asthma in patients and animals.MethodsStudies 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 employed to address the impact of CHOP deficiency on the development of asthma. Next, the effect of CHOP deficiency on macrophage polarization and related signaling pathways were investigated to demonstrate the underlying mechanisms.ResultsAsthmatic 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 hyper-responsiveness. CHOP was found to exacerbate allergic airway inflammation by enhancing M2 programming in macrophages. Mechanistic studies characterized an interleukin-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4Rα (IL-4/STAT6/Tfec/IL-4Rα) positive feedback regulatory loop, in which IL-4 induces CHOP expression, which then promotes STAT6 signaling to transcribe Tfec expression, and Tfec transcribes IL-4Rα expression to promote M2 programming in macrophages.ConclusionsCHOP and ER stress are implicated in asthma pathogenesis, which involves the regulation of M2 programming in macrophages.

Teaser

CHOP exacerbates allergic asthma by regulating the IL-4/STAT6/Tfec/IL-4Rα positive feedback loop essential for M2 programming in macrophages, which are positively correlated with disease severity in asthmatic patients.


http://ift.tt/2ms73kT