Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury.
Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury.
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DOI：
10.1155/2022/2520348
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发表时间：
2022
影响因子：
--
通讯作者：
Fei, Guang-He
中科院分区：
文献类型：
--
作者：
Xu, Meng-Meng;Kang, Jia-Ying;Ji, Shuang;Wei, Yuan-Yuan;Wei, Si-Liang;Ye, Jing-Jing;Wang, Yue-Guo;Shen, Ji-Long;Wu, Hui-Mei;Fei, Guang-He
流感病毒感染是急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）的最强致病因素之一。然而，潜在的细胞和分子机制尚未阐明。在这项研究中，我们的目的是调查是否褪黑激素调节巨噬细胞极化，氧化应激，并通过激活载脂蛋白E/低密度脂蛋白受体（ApoE/LDLR）途径在流感A诱导的ALI焦亡。在此，野生型（WT）和ApoE-/-小鼠经气管内滴注甲型流感（H3 N2）并经腹膜内注射褪黑激素连续7天。在体外，WT和ApoE-/-鼠骨髓源性巨噬细胞（BMDM）在H3 N2刺激前用褪黑激素预处理。结果表明，褪黑激素管理显着减弱H3 N2引起的肺损伤，白细胞浸润和水肿;减少促炎M1标记物的表达;增强抗炎M2标记物;和转换肺泡巨噬细胞（AM）的极化从M1到M2表型。此外，褪黑激素抑制活性氧（ROS-）介导的细胞凋亡，表现为丙二醛（MDA）和ROS水平的下调以及NLRP 3/GSDMD途径和乳酸脱氢酶（LDH）释放的抑制。引人注目的是，当褪黑激素应用于H3 N2感染的巨噬细胞和小鼠时，ApoE/LDLR途径被激活。ApoE基因敲除主要消除褪黑激素对H3 N2诱导的ALI的保护作用及其对巨噬细胞极化、氧化应激和焦亡的调节能力。此外，重组ApoE 3（re-ApoE 3）抑制H3 N2诱导的M1极化的BMDM与MT 1和MT 2的表达上调，但re-ApoE 2和re-ApoE 4未能做到这一点。褪黑素与re-ApoE 3组合在调节H3 N2感染的ApoE-/-BMDM中的巨噬细胞极化、氧化应激和焦亡方面发挥更有益的保护作用。我们的研究表明，褪黑素通过激活ApoE/LDLR通路抑制肺巨噬细胞M1极化和ROS介导的焦亡，减轻甲型流感（H3 N2）所致的ALI。本研究提示褪黑素-ApoE/LDLR轴可能成为流感病毒诱导的急性肺损伤的一种新的治疗策略。
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.
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影响因子：
--
作者：
Ni JQ;Ouyang Q;Lin L;Huang Z;Lu H;Chen X;Lin H;Wang Z;Xu D;Zhang Y
通讯作者：
Zhang Y
ResolvinD1 通过 Nrf2 途径保护气道屏障免受甲型流感病毒引起的损伤。
影响因子：
5.7
作者：
Guo Y;Tu YH;Wu X;Ji S;Shen JL;Wu HM;Fei GH
通讯作者：
Fei GH
影响因子：
4.4
作者：
Caini S;Kroneman M;Wiegers T;El Guerche-Séblain C;Paget J
通讯作者：
Paget J
影响因子：
4.4
作者：
Chotpitayasunondh T;Fischer TK;Heraud JM;Hurt AC;Monto AS;Osterhaus A;Shu Y;Tam JS
通讯作者：
Tam JS
影响因子：
6.1
作者：
Huang, Yadong;Mahley, Robert W.
通讯作者：
Mahley, Robert W.