Abstract
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.
Highlights
Sustained neuroinflammation is one of the most striking hallmarks shared by various neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD)
Neuroinflammation is a major neuropathological hallmark of neurodegenerative disorders, whereas brain renin–angiotensin system (RAS) now is found to play an essential role in an inflammatory response and becomes an emerging therapeutic target in brain aging
We previously demonstrated that blocking angiotensin type 1 receptor (AT1) receptor by candesartan is effective to attenuate LPS- induced exaggerated neuroinflammation and AngII is treated as part of the proinflammatory mediator in microglial response (Gong et al, 2019)
Summary
Sustained neuroinflammation is one of the most striking hallmarks shared by various neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The excessive inflammatory response can be counterbalanced by the RAS protective component, Ang(1–7), which exerts its effects through MasR, a G protein-coupled receptor, in various tissues, including the kidneys, cardiovascular system, and brain (Santos et al, 2018). It seems very likely the balance between the two arms of RAS plays an essential role in neuroinflammation, there is no research that systematically examined the expression of these RAS members during inflammatory process and the immune-regulatory mechanisms remain largely obscure. We try to explore the immune-regulatory mechanism of ACE2/Ang(1–7)/MasR axis by analyzing the interaction between ACE2/Ang(1–7)/MasR axis and autophagy in the development and treatment of neuroinflammation
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