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.

Ruili Dang, Mengqi Yang, Changmeng Cui, Changshui Wang, Wenyuan Zhang, Chunmei Geng, Wenxiu Han, Pei Jiang

Aging cell 2021 Oct

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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. © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Citation

Ruili Dang, Mengqi Yang, Changmeng Cui, Changshui Wang, Wenyuan Zhang, Chunmei Geng, Wenxiu Han, Pei Jiang. 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. Aging cell. 2021 Oct;20(10):e13480