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首页> 外文期刊>Aging cell. >Activation of angiotensin-converting enzyme 2/angiotensin (1–7)/mas receptor axis triggers autophagy and suppresses microglia proinflammatory polarization via forkhead box class O1 signaling
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Activation of angiotensin-converting enzyme 2/angiotensin (1–7)/mas receptor axis triggers autophagy and suppresses microglia proinflammatory polarization via forkhead box class O1 signaling

机译：血管紧张素转化酶2 /血管紧张素（1-7）/ MAS受体轴的激活触发自噬并抑制通过FORKHEAD箱类O1信号传导的微胶质促炎偏振

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Brain renin-angiotensin (Ang) system (RAS) is implicated in neuroinflammation, a major characteristic of aging process. Angiotensin (Ang) II, produced by angiotensin-converting enzyme (ACE), activates immune system via angiotensin type 1 receptor (AT1), whereas Ang(1–7), generated by ACE2, binds with Mas receptor (MasR) to restrain excessive inflammatory response. Therefore, the present study aims to explore the relationship between RAS and neuroinflammation. We found that repeated lipopolysaccharide (LPS) treatment shifted the balance between ACE/Ang II/AT1 and ACE2/Ang(1–7)/MasR axis to the deleterious side and treatment with either MasR agonist, AVE0991 (AVE) or ACE2 activator, diminazene aceturate, exhibited strong neuroprotective actions. Mechanically, activation of ACE2/Ang(1–7)/MasR axis triggered the Forkhead box class O1 (FOXO1)-autophagy pathway and induced superoxide dismutase (SOD) and catalase (CAT), the FOXO1-targeted antioxidant enzymes. Meanwhile, knockdown of MasR or FOXO1 in BV2 cells, or using the selective FOXO1 inhibitor, AS1842856, in animals, suppressed FOXO1 translocation and compromised the autophagic process induced by MasR activation. We further used chloroquine (CQ) to block autophagy and showed that suppressing either FOXO1 or autophagy abrogated the anti-inflammatory action of AVE. Likewise, Ang(1–7) also induced FOXO1 signaling and autophagic flux following LPS treatment in BV2 cells. Cotreatment with AS1842856 or CQ all led to autophagic inhibition and thereby abolished Ang(1–7)-induced remission on NLRP3 inflammasome activation caused by LPS exposure, shifting the microglial polarization from M1 to M2 phenotype. Collectively, these results firstly illustrated the mechanism of ACE2/Ang(1–7)/MasR axis in neuroinflammation, strongly indicating the involvement of FOXO1-mediated autophagy in the neuroimmune-modulating effects triggered by MasR activation.
机译：脑肾素 - 血管紧张素（ANG）系统（RAS）涉及神经炎症，衰老过程的主要特征。由血管紧张素转换酶（ACE）产生的血管紧张素（ANG）II通过血管紧张素1型受体（AT1）激活免疫系统，而由ACE2产生的ANG（1-7）与MAS受体（MASR）结合以抑制过多炎症反应。因此，本研究旨在探讨RAS与神经引起的关系。我们发现重复的脂多糖（LPS）治疗将ACE / Ang II / AT1和ACE2 / An（1-7）/ MasR轴之间的平衡转移到有害侧，并用MasR激动剂，AVE0991（AVE）或ACE2活化剂处理，二亚嗪醋酸盐，表现出强烈的神经保护作用。机械地，ACE2 / ANG（1-7）/ MASR轴的激活引发了叉头箱类O1（FOXO1） - 分配途径和诱导超氧化物歧化酶（SOD）和过氧化氢酶（猫），FOXO1靶向抗氧化酶。同时，在BV2细胞中敲低MasR或FoxO1，或使用选择性FoxO1抑​​制剂，As1842856，动物，抑制FoxO1易位并损害了MasR活化诱导的自噬过程。我们进一步使用氯喹（CQ）阻断自噬，并显示抑制FoxO1或自噬废除Ave的抗炎作用。同样地，Ang（1-7）在BV2细胞中的LPS处理后也诱导FoxO1信号传导和自噬助焊剂。具有AS1842856或CQ的CoTreatment所有导致自噬抑制，从而废除了Ang（1-7）诱导的LPS暴露引起的NLRP3炎性激活的缓解，使M1至M2表型移位微胶质极化。总的来说，这些结果首先说明了神经引起的ACE2 / Ang（1-7）/ MasR轴的机制，强烈指示FoxO1介导的自噬在于MasR活化引发的神经免疫调节效果。

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