Journal Article

Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis

Zhang, Da-Wei, Kang, Jia-Ying, Wang, Qiu-Yan, Fei, Guang-He, Wu, Hui-Mei, Wei, Yuan-Yuan, Zhang, Ling, Xu, Meng-Meng, Zuo, Xing, Tan, Yuan-Yuan

2024

Overview

Background Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. Methods COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. Results The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV 20,50 /FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1β attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling via MTs. Conclusions These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1β/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD. Graphical Abstract Schematic mechanisms underlying the regulatory effects of melatonin on macrophage polarization and apoptosis in IAV infection plus cigarette stimulation-induced AECOPD model.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Air flow / Alveoli / Analysis / Animal models / Animals / Apoptosis / Apoptosis - drug effects / Atomizing / Bronchus / Cell Polarity - drug effects / Chronic infection / Chronic obstructive pulmonary disease / Cigarette smoke / Cigarette smoking / Cigarettes / Complications and side effects / Cytokine storm / Disease Models, Animal / Disease Progression / Enzyme inhibitors / Enzymes / Epidemics / Ethylenediaminetetraacetic acid / Flow cytometry / Health aspects / IL-1β / Infections / Inflammation / Influenza / Influenza A / Influenza A Virus, H3N2 Subtype - drug effects / Influenza virus / Influenza viruses / Injuries / Interleukin-1β / Interleukins / Laboratory animals / Lavage / Leukocytes / Lung diseases / Lung diseases, Obstructive / Lungs / Macrophage polarization / Macrophages / Macrophages - drug effects / Macrophages - metabolism / Macrophages, Alveolar - drug effects / Macrophages, Alveolar - metabolism / Macrophages, Alveolar - virology / Male / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Melatonin / Melatonin - pharmacology / Melatonin receptors / Mice / Mice, Inbred C57BL / Neutrophils / Original / Original Article / Orthomyxoviridae Infections - drug therapy / Orthomyxoviridae Infections - immunology / Orthomyxoviridae Infections - metabolism / Pathogens / Pharmacology / Phosphorylation / Physiological aspects / Pneumology/Respiratory System / Polarization / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - metabolism / Pulmonary Disease, Chronic Obstructive - physiopathology / Pulmonary Disease, Chronic Obstructive - virology / RAW 264.7 Cells / Respiratory function / Signal transduction / Smoking / Stat1 protein / Trachea / Viruses