Erythromycin suppresses neutrophil extracellular traps in smoking-related chronic pulmonary inflammation

Hui Zhang,Xiu Zhou,Jing Bai,Mei-Hua Li,Shi-Lin Qiu,Xiao-Ning Zhong,Jian-Quan Zhang,Qi-Ya Tang,Yi Liang,Jing-Min Deng,Zhi-Yi He

doi:10.1038/s41419-019-1909-2

Abstract

Neutrophil extracellular traps (NETs) may play a critical role in smoking-related chronic airway inflammation. However, the mechanism by which NETs induced by cigarette smoke initiate the adaptive immunity in chronic obstructive pulmonary disease (COPD) is not fully understood. In this study, we explored the effects of NETs induced by cigarette smoke on the myeloid dendritic cells (mDCs) and Th1 and Th17 cells. Additionally, we observed the inhibitory effect of erythromycin on NETs induced by cigarette smoke. We found that elevated NET levels in the sputum of COPD patients were correlated with the circulating Th1 response, mDC activation and airflow limitation. NETs induced by cigarette smoke extract (CSE) could activate monocyte-derived mDCs and promote Th1 and Th17 differentiation in vitro. Erythromycin effectively inhibited NET formation induced by CSE. In vivo, erythromycin decreased NETs in the airway and ameliorated emphysema with Th1 and Th17 cell down-regulation and CD40+ and CD86+ mDCs suppression in mice chronically exposed to cigarette smoke. These findings provide direct evidence that NETs promote the differentiation of Th1 and Th17 and play a role in the adaptive immunity of smoking-related chronic lung inflammation. Erythromycin is a potential therapeutic strategy for NETs inhibition in COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with abnormal airway and alveolar inflammatory responses to cigarette smoke or other noxious particles and gases[1]
We previously observed that polymorphonuclear neutrophils (PMNs) of mice with emphysema seem to be highly sensitive to Neutrophil extracellular traps (NETs) production[16]
NET formation can be considered a protective strategy by the host in response to invading pathogens or, in response to tissue damage caused by other harmful environmental irritants

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with abnormal airway and alveolar inflammatory responses to cigarette smoke or other noxious particles and gases[1]. Cigarette smoking is the major risk factor for COPD and directly promotes airway neutrophilic inflammation[3]. Studies have indicated that NETs are involved in many non-infectious disorders and chronic inflammatory conditions, such as systemic lupus erythematosus[7], autoimmune small-vessel vasculitis[8], rheumatoid arthritis[9], atherosclerosis[10], and others[11,12,13,14]. Previous studies have revealed that excessive NETs in the sputum are associated with elevated pro-inflammatory cytokine levels and might contribute to lung damage[15,16]

Methods

Results

Conclusion