Synergistic cycles of protease activity and inflammation via PPAR\u03b3 degradation in chronic obstructive pulmonary disease

Nakwon Kwak,Jisu Woo,Chang-Hoon Lee,Jiyeon Kim,Chul-Gyu Yoo,Kyoung-Hee Lee

doi:10.1038/s12276-021-00626-7

Abstract

Inflammation, oxidative stress, and protease–antiprotease imbalance have been suggested to be a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, it is not clear how proteases interact with components of inflammatory pathways. Therefore, this study aimed to evaluate the effect of neutrophil elastase (NE) on lipopolysaccharide (LPS)-induced interleukin 8 (IL-8) production and determine the molecular mechanism in human bronchial epithelial cells (HBECs). Immortalized bronchial epithelial cells and primary HBECs were used to investigate the impact of NE on LPS-induced IL-8 production. The molecular mechanism by which NE modulated LPS-induced IL-8 production was confirmed in elastase-treated C57BL/6 mice and primary HBECs obtained from COPD patients and healthy controls. The results showed that NE treatment synergistically augmented LPS-induced IL-8 production in both immortalized bronchial epithelial cells and primary HBECs. NE partially degraded peroxisome proliferator-activated receptor gamma (PPARγ), which is known to regulate IL-8 production in the nucleus. Treatment with a PPARγ agonist and overexpression of PPARγ reversed the NE-induced synergistic increase in LPS-induced IL-8 production. Moreover, PPARγ levels were lower in lung homogenates and lung epithelial cells from elastase-treated mice than in those from saline-treated mice. In accordance with the findings in mice, PPARγ levels were lower in primary HBECs from COPD patients than in those from healthy never-smokers or healthy smokers. In conclusion, a vicious cycle of mutual augmentation of protease activity and inflammation resulting from PPARγ degradation plays a role in the pathogenesis of COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease characterized by persistent respiratory symptoms and airflow limitations[1]
While treatment with neutrophil elastase (NE) alone did not affect the level of interleukin 8 (IL-8), pretreatment with NE for 4 h augmented the LPS-induced production of IL-8 in both BEAS-2B cells and primary human bronchial epithelial cells (HBECs) (Fig. 1)
Since it is well known that LPS first binds to TLR4, which activates the IκB/NF-κB pathway to result in IL-8 production[15], whether the TLR4 or ΙκB/NFκB pathway was involved in mediating the NE-mediated synergistic increase in LPS-induced IL-8 production was tested

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease characterized by persistent respiratory symptoms and airflow limitations[1]. The pathogenesis of COPD is complex, and inflammation, oxidative stress, and protease–antiprotease imbalance have been suggested to be a pathogenic triad in COPD2 Within this triad, the most well-known type of pathogenesis associated with COPD is chronic inflammation (TLRs), stimulating an innate immune response that leads to the recruitment of neutrophils and macrophages to the lungs[3] and activates airway epithelial cells[3]. The most well-known type of pathogenesis associated with COPD is chronic inflammation (TLRs), stimulating an innate immune response that leads to the recruitment of neutrophils and macrophages to the lungs[3] and activates airway epithelial cells[3] Activation of these cells triggers the release of various inflammatory cytokines, such as interleukin 8 (IL-8), which acts as a chemoattractant for neutrophils; these recruited neutrophils perpetuate chronic inflammation in COPD4,5.

Objectives

Methods

Results

Conclusion