Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma

Abstract

Introduction: Endoplasmic reticulum (ER) stress has been considered to be an important regulator of airway inflammation in the pathogenesis of bronchial asthma, but the mechanism of ER stress involved in neutrophilic asthma remain not fully understood. Methods: Tunicamycin is a mixture of homologous nucleoside antibiotics, which is used to induce ER stress. In the present study, Tunicamycin was administered to mouse bronchial epithelial cells and a neutrophilic asthma model (OVA_LPS-OVA mice), and ER stress indicators and inflammatory cytokines were measured by Western blotting and Elisa. Results: Tunicamycin not only induced ER stress in mouse bronchial epithelial cells, but also increased expression of inflammation indicators such as IL-6, IL-8, and TNF-α via PERK-ATF4-CHOP signaling. Additionally, the phosphorylation of PERK and the expression levels of ATF4 and CHOP proteins and inflammatory cytokines (IL-6, IL-8 and TNF-α) were elevated in the lung tissue of OVA_LPS-OVA mice. Administering tunicamycin further increased protein expression levels of ER stress indicators and inflammatory cytokines, and resulted in more severe asthma phenotypes in OVA_LPS-OVA mice, suggesting that PERK-ATF4-CHOP signaling is associated with airway inflammation in neutrophil-dominant asthma. Conclusions: These data support the emerging notion that regulation of ER stress could be strongly associated with the development of neutrophilic asthma.

KEYWORDS:

• Airway inflammation
• ER stress
• inflammatory cytokine
• neutrophilic asthma
• PERK-ATF4-CHOP signaling
• tunicamycin

Acknowledgements

BZ participated in the design of the study, researched data, performed the statistical analysis and wrote the manuscript. QG carried out the molecular and animal studies and drafted the manuscript. HL and JL carried out the molecular and animal studies. LX, LY and ZS participated in the design of the study, researched data and performed the statistical analysis. All authors read and approved the final manuscript.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

This work was supported by the programs from the National Natural Science Foundation of China (General Program no. 81170073 and 81500016), and the Young Innovators Awards of the First Affiliated Hospital of Xi'an Jiaotong University (2014YK3 and 2015YK6).