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


Abstract

Background

Influenza A viruses (IAVs) are highly common respiratory viruses for acute exacerbation of chronic obstructive pulmonary disease (COPD), where IAV infection can cause abnormal macrophage polarization and amplify cytokine storms. Melatonin exerts potential anti-inflammatory and anti-IAV effects, while its effects on IAV infection-induced AECOPD are not well understood.

Methods

COPD mouse models were established by cigarette smoke exposure for 24 consecutive weeks, evaluated by lung function detection. AECOPD mouse models were established by intratracheal atomization of influenza A/H3N2 virus stocks in COPD mice and injected with melatonin (Mel) intraperitoneally. Then, alveolar macrophage (AM) polarization was analyzed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization in CSE-stimulated Raw264.7 macrophages infected with IAV were analyzed. Additionally, the roles of melatonin receptors (MT) in regulating macrophage polarization and apoptosis were determined using luzindole, an MT antagonist.

Results

The current results demonstrated that H3N2 IAV infection impaired lung function (FEV1). /FVC ratio), exacerbated lung damage in COPD mice with increased dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damage in AECOPD mice by decreasing influenza A nucleoprotein (IAV-NP) protein levels and M1 polarization of lung macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted dual macrophage polarization accompanied by decreased MT1 expression. Melatonin reduced STAT1 phosphorylation, M1 marker levels, and IAV-NP levels through MT were reflected by the addition of luzindole. Recombinant IL-1β attenuated melatonin’s inhibitory effects on IAV infection and STAT1-driven M1 polarization, while its enzyme inhibitor VX765 potentiated melatonin’s inhibitory effects on them. Additionally, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1β/STAT1 signaling through MT.

Conclusions

These findings suggested that melatonin inhibited IAV infection, improved lung function, and lung damage of AECOPD by suppressing M1 macrophage polarization and apoptosis driven by IL-1β/STAT1 in an MT-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza-induced AECOPD.

Graphical Abstract

Schematic mechanisms underlying the regulatory effects of melatonin on macrophage polarization and apoptosis in IAV infection plus cigarette smoke stimulation-induced AECOPD model.

Introduction

Influenza virus infection, an extremely detrimental public health problem, causes a huge burden of morbidity worldwide. The World Health Organization (WHO) estimated that seasonal influenza affected 57% of the global population, causing approximately 3 to 5 million severe cases and between 290,000 and 650,000 respiratory deaths per year (1, 2), especially among elderly adults with chronic obstructive pulmonary disease (COPD) (3, 4). Our previous study confirmed that influenza A virus (IAV) was the most common respiratory virus associated with acute exacerbation of COPD (AECOPD) in Asia (5).

Influenza viruses are mainly divided into three types (A, B, and C), among which influenza A and B viruses are prone to cause seasonal influenza epidemics (6). Currently, influenza type A viruses (H1N1 and H3N2) account for the majority of influenza epidemics worldwide. In mainland China, influenza A/H3N2 subtypes exhibited the longest average epidemic duration of approximately 4.83 months/year, followed by influenza B and A/H1N1 viruses (2, 7, 8). Additionally, the excess respiratory deaths associated with influenza A/H3N2 were the highest, 80% of which occurred in individuals aged ≥ 60 years (9). Therefore, it is of great importance to explore the potential molecular mechanisms and effective therapeutic agents against AECOPD triggered by IAV infection.

Influenza virus infection is extremely prone to induce lung epithelial injury and leukocyte infiltration, resulting in cytokine storms in the airways or «hypercytokinemia» (10). As highly plastic innate immune cells, macrophages form the first immune lines against virus and bacterial infections. Macrophages can polarize into multifunctional phenotypes depending on different stimuli (11). Cigarette irritation induces polarization of lung macrophages into classically activated (M1 type, commonly activated by signal transducer and activator of transcription 1 (STAT1) signaling12, 13). Activated STAT1 signaling drives the expression of characteristic M1 genes, such as inducible nitric oxide synthase (iNOS), CD86, monocyte chemoattractant protein 1 (MCP1), and interleukin-1β (IL-1β), causing pulmonary inflammatory damage, including apoptosis, exacerbating COPD lung disease damages (14). Alternatively, alternatively activated (M2 type) macrophages are also closely related to lung damages in COPD (14, 15). Alveolar macrophages (AM) M2 are commonly evoked through signal transducer and activator of transcription 6 (STAT6) signaling, driving the expression of M2 markers (IL-4, CD206, arginase 1 (Arg1), and TGF-β, etc.) with the formation of fibroproliferative microenvironments. The difference in airway microenvironments determines the proportion of M1 and M2 macrophages, also affecting the «injury-repair» process of lung tissues (16, 17). Our recent study revealed that acute IAV infection induced acute lung injury (ALI) by enhancing M1 polarization of lung macrophages and inhib

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