PMID- 36425057 OWN - NLM STAT- MEDLINE DCOM- 20221129 LR - 20221129 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2022 DP - 2022 TI - Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury. PG - 2520348 LID - 10.1155/2022/2520348 [doi] LID - 2520348 AB - Influenza virus infection is one of the strongest pathogenic factors for the development of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). However, the underlying cellular and molecular mechanisms have not been clarified. In this study, we aim to investigate whether melatonin modulates macrophage polarization, oxidative stress, and pyroptosis via activating Apolipoprotein E/low-density lipoprotein receptor (ApoE/LDLR) pathway in influenza A-induced ALI. Here, wild-type (WT) and ApoE-/- mice were instilled intratracheally with influenza A (H3N2) and injected intraperitoneally with melatonin for 7 consecutive days. In vitro, WT and ApoE-/- murine bone marrow-derived macrophages (BMDMs) were pretreated with melatonin before H3N2 stimulation. The results showed that melatonin administration significantly attenuated H3N2-induced pulmonary damage, leukocyte infiltration, and edema; decreased the expression of proinflammatory M1 markers; enhanced anti-inflammatory M2 markers; and switched the polarization of alveolar macrophages (AMs) from M1 to M2 phenotype. Additionally, melatonin inhibited reactive oxygen species- (ROS-) mediated pyroptosis shown by downregulation of malonaldehyde (MDA) and ROS levels as well as inhibition of the NLRP3/GSDMD pathway and lactate dehydrogenase (LDH) release. Strikingly, the ApoE/LDLR pathway was activated when melatonin was applied in H3N2-infected macrophages and mice. ApoE knockout mostly abrogated the protective impacts of melatonin on H3N2-induced ALI and its regulatory ability on macrophage polarization, oxidative stress, and pyroptosis. Furthermore, recombinant ApoE3 (re-ApoE3) inhibited H3N2-induced M1 polarization of BMDMs with upregulation of MT1 and MT2 expression, but re-ApoE2 and re-ApoE4 failed to do this. Melatonin combined with re-ApoE3 played more beneficial protective effects on modulating macrophage polarization, oxidative stress, and pyroptosis in H3N2-infected ApoE-/- BMDMs. Our study indicated that melatonin attenuated influenza A- (H3N2-) induced ALI by inhibiting the M1 polarization of pulmonary macrophages and ROS-mediated pyroptosis via activating the ApoE/LDLR pathway. This study suggested that melatonin-ApoE/LDLR axis may serve as a novel therapeutic strategy for influenza virus-induced ALI. CI - Copyright (c) 2022 Meng-Meng Xu et al. FAU - Xu, Meng-Meng AU - Xu MM AUID- ORCID: 0000-0001-6699-4499 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Kang, Jia-Ying AU - Kang JY AUID- ORCID: 0000-0002-8802-3674 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Ji, Shuang AU - Ji S AUID- ORCID: 0000-0001-6145-2244 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Wei, Yuan-Yuan AU - Wei YY AUID- ORCID: 0000-0002-3414-0963 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Wei, Si-Liang AU - Wei SL AUID- ORCID: 0000-0003-1101-0290 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Ye, Jing-Jing AU - Ye JJ AUID- ORCID: 0000-0002-7984-3670 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Wang, Yue-Guo AU - Wang YG AUID- ORCID: 0000-0002-6297-9782 AD - Department of Emergency Critical Care Medicine, First Affiliated Hospital of Anhui Provincial Hospital, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230001 Anhui, China. FAU - Shen, Ji-Long AU - Shen JL AUID- ORCID: 0000-0002-4755-3687 AD - Provincial Laboratory of Microbiology and Parasitology of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Wu, Hui-Mei AU - Wu HM AUID- ORCID: 0000-0001-8149-6674 AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Anhui Geriatric Institute, Department of Geriatric Respiratory Critical and Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. FAU - Fei, Guang-He AU - Fei GH AUID- ORCID: 0000-0003-0064-2073 AD - Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. AD - Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022 Anhui, China. LA - eng PT - Journal Article DEP - 20221115 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (Apolipoprotein E3) RN - 0 (Apolipoproteins E) RN - JL5DK93RCL (Melatonin) RN - 0 (Reactive Oxygen Species) SB - IM MH - Animals MH - Mice MH - *Acute Lung Injury/drug therapy/metabolism/virology MH - Apolipoprotein E3/pharmacology MH - Apolipoproteins E/metabolism MH - Influenza A Virus, H3N2 Subtype MH - Macrophages/metabolism MH - *Melatonin/therapeutic use MH - Mice, Knockout, ApoE MH - Pyroptosis MH - Reactive Oxygen Species/metabolism MH - *Orthomyxoviridae Infections/drug therapy PMC - PMC9681554 COIS- All authors declared no competing interests in the current study. EDAT- 2022/11/26 06:00 MHDA- 2022/11/29 06:00 PMCR- 2022/11/15 CRDT- 2022/11/25 02:37 PHST- 2022/06/24 00:00 [received] PHST- 2022/10/07 00:00 [accepted] PHST- 2022/11/25 02:37 [entrez] PHST- 2022/11/26 06:00 [pubmed] PHST- 2022/11/29 06:00 [medline] PHST- 2022/11/15 00:00 [pmc-release] AID - 10.1155/2022/2520348 [doi] PST - epublish SO - Oxid Med Cell Longev. 2022 Nov 15;2022:2520348. doi: 10.1155/2022/2520348. eCollection 2022.