Melatonin regulates microglial M1/M2 polarization via AMPKα2-mediated mitophagy in attenuating sepsis-associated encephalopathy - 23/07/24
, Jinyong Ke , Yang Cao , Yue Gao , Chunshui Lin ⁎ Abstract |
Background |
Sepsis-associated encephalopathy (SAE) is a disease characterized by neuroinflammation and cognitive dysfunction caused by systemic infection. Inflammation-induced microglial activation is closely associated with neuroinflammation in SAE. It is widely understood that melatonin has strong anti-inflammatory and immunomodulatory properties beneficial for sepsis-related brain damage. However, the mechanism of melatonin action in SAE has not been fully elucidated.
Methods |
The SAE cell model and SAE mouse model were induced by lipopolysaccharide (LPS). Behavioral tests were performed to analyze cognitive function. Microglial markers and M1/M2 markers were measured by immunofluorescence. Mitophagy was assessed by western blot, mt-Keima and transmission electron microscopy experiments. Immunoprecipitation and co-immunoprecipitation assays investigated the interactions between AMP-activated protein kinase α2 (AMPKα2) and PTEN-induced putative kinase 1 (PINK1).
Results |
Melatonin suppresses LPS-induced microglia M1 polarization by enhancing mitophagy, thereby attenuating LPS-induced neuroinflammation and behavioral deficits. However, inhibition or knockdown of AMPKα2 can inhibit the enhancement of melatonin on mitophagy, then weaken its promotion of microglia polarization towards M2 phenotype, and eliminate its protective effect on brain function. Furthermore, melatonin enhances mitophagy through activating AMPKα2, promotes PINK1 Ser495 site phosphorylation, and ultimately regulates microglial polarization from M1 to M2.
Conclusions |
Our findings demonstrate that melatonin facilitates microglia polarization towards M2 phenotype to alleviate LPS-induced neuroinflammation, primarily through AMPKα2-mediated enhancement of mitophagy.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Schematic model of the mechanism by which melatonin regulates LPS-induced microglial polarization and neuroinflammation by enhancing AMPKα2-mediated mitophagy via PINK1 phosphorylation. LPS: lipopolysaccharide; PINK1: PTEN-induced putative protein kinase 1.
Schematic model of the mechanism by which melatonin regulates LPS-induced microglial polarization and neuroinflammation by enhancing AMPKα2-mediated mitophagy via PINK1 phosphorylation. LPS: lipopolysaccharide; PINK1: PTEN-induced putative protein kinase 1.Le texte complet de cet article est disponible en PDF.
Highlights |
• | Melatonin mitigates neuroinflammation and cognitive impairments in SAE by regulating microglia polarization via mitophagy. |
• | Activation of AMPKα2 mediates melatonin-induced mitophagy in SAE. |
• | AMPKa2 activation suppresses M1 and promotes M2 microglial polarization via mitophagy through PINK1-Ser495 phosphorylation. |
• | Targeting melatonin and AMPK holds therapeutic promise for treating neuroinflammation and cognitive dysfunction. |
Abbreviations : SAE, Arg-1, LC3, TNF-α, IL-6, iNOS, IFN-γ, IL-10, IL-1β, TGF-β, WT, LPS, PINK1, Mel, AMPK, 3-MA, Iba-1, CNV, iPSC, ULK1, BBB
Keywords : Sepsis-associated encephalopathy, Melatonin, AMPKα2, Mitophagy, Microglial polarization, PINK1
Plan
Vol 177
Article 117092- août 2024 Retour au numéro
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