Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 62, Issue -, Pages 277-290Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2017.02.013
Keywords
Angiotensin; Astrocytes; Dopaminergic; Immunomodulation; Microglia; NADPH-oxidase; Neuroinflammation; Microglia; Parkinson; Aging
Categories
Funding
- Spanish Ministry of Economy and Competitiveness [BFU2015-70523]
- Spanish Ministry of Health [RD12/0019/0020, RD16/0011/0016]
- CIBERNED
- Galician Government (XUGA), Spain [GRC2014/002]
- FEDER (Regional European Development Fund, European Union)
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Dopamine is an immunomodulatory molecule that acts on immune effector cells both in the CNS and peripheral tissues. However, the role of changes in dopamine levels in the neuroinflammatory response is controversial. The local/paracrine renin-angiotensin system (RAS) plays a major role in inflammatory processes in peripheral tissues and brain. In the present study, we investigated the possible role of the brain RAS in the effects of dopamine on the glial inflammatory responses. Astrocytes are the major source of the precursor protein angiotensinogen and angiotensin II (AII) in the brain. Neurotoxins such as MPP+ (1-methyl-4-phenylpyridinium) can act directly on astrocytes to increase levels of angiotensinogen and All. Conversely, dopamine, via type-2 (D2) receptors, inhibited production of angiotensinogen, decreased expression of angiotensin type-1 (AT1) receptors and increased expression of AT2 receptors. In microglia, dopamine and dopamine agonists also regulated RAS activity. First, indirectly, via downregulation of the astrocyte-derived All. Second, via dopamine-induced regulation of microglial angiotensin receptors. Dopamine decreased the microglial AT1/AT2 ratio leading to inhibition of the pro-inflammatory AT1/NADPH-oxidase/superoxide axis. D2 receptors were particularly responsible for microglial RAS inhibition in basal culture conditions. However, both D1 and D2 agonists inhibited the AT1/NADPH-oxidase axis in lipopolysaccharide-treated (LPS; i.e. activated) microglia. The results indicate that the decrease in dopamine levels observed in early stages of Parkinson ' s disease and aging may promote neuroinflammation and disease progression via glial RAS exacerbation. (C) 2017 Elsevier Inc. All rights reserved.
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