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Microglial MT1 activation inhibits LPS‐induced neuroinflammation via regulation of metabolic reprogramming
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Microglial MT1 activation inhibits LPS‐induced neuroinflammation via regulation of metabolic reprogramming
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Journal Article
Microglial MT1 activation inhibits LPS‐induced neuroinflammation via regulation of metabolic reprogramming
2021
Overview
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Although its pathogenesis remains unclear, a number of studies indicate that microglia‐mediated neuroinflammation makes a great contribution to the pathogenesis of PD. Melatonin receptor 1 (MT1) is widely expressed in glia cells and neurons in substantia nigra (SN). Neuronal MT1 is a neuroprotective factor, but it remains largely unknown whether dysfunction of microglial MT1 is involved in the PD pathogenesis. Here, we found that MT1 was reduced in microglia of SN in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model. Microglial MT1 activation dramatically inhibited lipopolysaccharide (LPS)‐induced neuroinflammation, whereas loss of microglial MT1 aggravated it. Metabolic reprogramming of microglia was found to contribute to the anti‐inflammatory effects of MT1 activation. LPS‐induced excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS) could be reversed by microglial MT1 activation. MT1 positively regulated pyruvate dehydrogenase alpha 1 (PDHA1) expression to enhance OXPHOS and suppress aerobic glycolysis. Furthermore, in LPS‐treated microglia, MT1 activation decreased the toxicity of conditioned media to the dopaminergic (DA) cell line MES23.5. Most importantly, the anti‐inflammatory effects of MT1 activation were observed in LPS‐stimulated mouse model. In general, our study demonstrates that MT1 activation inhibits LPS‐induced microglial activation through regulating its metabolic reprogramming, which provides a mechanistic insight for microglial MT1 in anti‐inflammation.
A schematic diagram shows the involvement of metabolic reprogramming in MT1 activation‐mediated inhibition of LPS‐induced microglial activation. Once microglia suffered LPS insults, microglia would transfer into over‐activated state, accompanied by converting their metabolic status from OXPHOS to aerobic glycolysis. However, microglial MT1 activation could promote PDHA1 expression, leading to reverse LPS‐mediated microglial metabolic reprogramming, thereby, suppressing microglial activation.
Publisher
Wiley,John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Animals
/ Brain
/ Indenes
/ Lipopolysaccharides - antagonists & inhibitors
/ Lipopolysaccharides - pharmacology
/ Male
/ Mice
/ MPTP
/ MT1
/ Neurodegenerative Diseases - drug therapy
/ Neurodegenerative Diseases - genetics
/ Neurodegenerative Diseases - metabolism
/ Neurodegenerative Diseases - pathology
/ Original
/ Parkinson Disease - drug therapy
/ Parkinson Disease - genetics
/ Parkinson Disease - metabolism
/ Parkinson Disease - pathology
/ PDHA1
/ Proteins
/ Receptor, Melatonin, MT1 - agonists
