Journal ArticleDOI
AT2R Activation Prevents Microglia Pro-inflammatory Activation in a NOX-Dependent Manner: Inhibition of PKC Activation and p47 phox Phosphorylation by PP2A
TLDR
It is suggested that AT2R, via PP2A-mediated inhibition of PKC, prevents the NOX activation, ROS generation, and subsequent pro-inflammatory activation of microglia.Abstract:
Microglia-induced reactive oxygen species (ROS) production and inflammation play an imperative role in neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). It has been established that angiotensin II type-2 receptor (AT2R) activation is neuroprotective in central nervous system diseases like stroke and AD. However, the involvement of AT2R in NADPH oxidase (NOX)-mediated microglia activation is still elusive. Therefore, the present study investigated the role of AT2R in angiotensin II (Ang II) or Phorbol 12-myristate 13-acetate (PMA)-induced microglia activation in BV2 cells, primary microglia, p47phox knockout (p47KO) microglia, and in vivo. Treatment of microglia with Ang II or PMA induced a significant ROS generation and promoted pro-inflammatory microglia in a NOX-dependent manner. In contrast, AT2R activation by CGP42112A (CGP) inhibited NOX activation, ROS production, and pro-inflammatory microglia activation, while promoting the immunoregulatory microglia. This inhibitory effect of AT2R on NOX and pro-inflammatory activation was attenuated by AT2R antagonist, PD123319. Essentially, NOX inhibition (by DPI) or scavenging cellular ROS (by NAC) or p47KO microglia were immune to Ang II- or PMA-induced pro-inflammatory microglia activation. Mechanistically, AT2R, via activation of protein phosphatase-2A (PP2A), prevented the Ang II- or PMA-induced protein kinase C (PKC) activation and phosphorylation of p47phox, an effect that was reversed by the addition of PP2A inhibitor, Okadaic acid (OA). Importantly, PKC inhibitor, Rottlerin, inhibited the Ang II- or PMA-induced p47phox phosphorylation and ROS generation to the similar extent as AT2R activation. In addition, AT2R activation or p47KO prevented ROS production, pro-inflammatory microglial activation, and sickness behavior in mice model of neuroinflammation. Therefore, the present findings suggested that AT2R, via PP2A-mediated inhibition of PKC, prevents the NOX activation, ROS generation, and subsequent pro-inflammatory activation of microglia.read more
Citations
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Journal ArticleDOI
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease.
TL;DR: It is suggested that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation and recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.
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Oxidative stress in neurodegeneration: cause or consequence?
TL;DR: The evidence for oxidative stress in neurodegeneration is reviewed and how this relates to other cellular events in the emerging roadmap leading to neurodegenesis is reviewed.
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Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system.
Changmeng Cui,Pengfei Xu,Gongying Li,Yi Qiao,Wenxiu Han,Chunmei Geng,Dehua Liao,Mengqi Yang,Dan Chen,Pei Jiang +9 more
TL;DR: Findings strongly indicate the involvement of ACE2/Ang(1–7)/MasR pathway in the neuroprotective mechanisms of VitD in the hypertensive brain.
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Effect of exercise on microglial activation and transcriptome of hippocampus in fluorosis mice.
TL;DR: Results indicate that treadmill running inhibits the excessive activation of microglia in hippocampus of the fluoride-toxic mice, accompanied with the alteration of neuroactive ligand-receptor interaction pathway.
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Glutaminase in microglia: A novel regulator of neuroinflammation.
TL;DR: Results indicate that GLS has more complicated implications in brain disease etiology than what is previously known, indicating microglial GLS as a promising target to treat these diseases.
References
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Journal ArticleDOI
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Karen Bedard,Karl-Heinz Krause +1 more
TL;DR: This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
Journal ArticleDOI
Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options.
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TL;DR: There is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators in neurodegenerative diseases.
Journal ArticleDOI
Oxidative stress in neurodegeneration: cause or consequence?
TL;DR: A review of the evidence for oxidative stress in neurodegeneration and how this relates to other cellular events can be found in this article, where a growing number of in vitro and in vivo models that emulate human disease pathology is aiding scientists in deciphering just where oxidative stress intersects with other cellular processes.
Journal ArticleDOI
Microglia in neurodegenerative disease
TL;DR: The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration, and could contribute to the outcome of neurodegenerative diseases.