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Mitochondrial Preparation from Microglia for Glycan Analysis
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Microglial MT1 activation inhibits LPS-induced neuroinflammation via regulation of metabolic reprogramming
Chao Gu1,2,3, Fen Wang2, Yu-Ting Zhang1,2
1Department of Neurology, Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
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.
Insights
Melatonin receptor 1 (MT1) activation in microglia reduces neuroinflammation in Parkinson's disease models. MT1 regulates microglial metabolism, suppressing harmful inflammation and protecting dopaminergic neurons.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Parkinson's disease (PD) pathogenesis involves microglia-mediated neuroinflammation.
- Melatonin receptor 1 (MT1) is present in substantia nigra glia and neurons.
- The role of microglial MT1 in PD is largely unknown.
Purpose of the Study:
- Investigate the role of microglial MT1 in PD pathogenesis.
- Determine if MT1 activation impacts microglial metabolism and neuroinflammation.
- Explore MT1's potential as a therapeutic target for PD.
Main Methods:
- Utilized a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model.
- Examined MT1 expression in microglia from the substantia nigra.
- Assessed the effects of MT1 activation/loss on lipopolysaccharide (LPS)-induced neuroinflammation and microglial metabolism.
- Investigated MT1's regulation of pyruvate dehydrogenase alpha 1 (PDHA1) expression.
- Evaluated the impact of MT1 activation on dopaminergic cell viability in vitro and in vivo.
Main Results:
- MT1 expression was reduced in microglia of MPTP-treated mice.
- MT1 activation inhibited LPS-induced neuroinflammation, while MT1 loss aggravated it.
- MT1 activation reversed LPS-induced metabolic changes, including excessive aerobic glycolysis and impaired oxidative phosphorylation (OXPHOS).
- MT1 positively regulated PDHA1 expression, enhancing OXPHOS and suppressing glycolysis.
- MT1 activation reduced conditioned media toxicity to dopaminergic cells and showed anti-inflammatory effects in an LPS-stimulated mouse model.
Conclusions:
- MT1 activation in microglia suppresses neuroinflammation by reprogramming microglial metabolism.
- MT1 regulates microglial metabolic pathways, specifically enhancing OXPHOS and reducing glycolysis via PDHA1.
- Microglial MT1 represents a potential therapeutic target for mitigating neuroinflammation in Parkinson's disease.
