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Published on: July 25, 2022
miR‑223‑3p promotes microglial lactylation and M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis
Xiaoyu Wang1, Lin Song1, Jiafeng Wang1
1Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China.
Abstract:
Neuroinflammation is a hallmark of Alzheimer's disease (AD) and is closely linked to microglial M1 polarization. In the present study, miR‑223‑3p was identified as a critical regulator of microglial metabolic reprogramming. Analyses of Gene Expression Omnibus and AD Neuroimaging Initiative datasets revealed significant upregulation of miR‑223‑3p in the brain, blood, and cerebrospinal fluid of patients with AD. The overexpression of miR‑223‑3p promoted M1 polarization and increased reactive oxygen species (ROS) levels. Transcriptomic, metabolomic and Seahorse analyses revealed increased glycolysis, lactate production and lactylation, whereas inhibition of lactylation reduced M1 polarization and ROS accumulation. Mechanistically, miR‑223‑3p suppressed SIRT1 expression and directly targeted FBXW7, leading to activation of the Notch1/Hes1 pathway and further suppression of SIRT1. In summary, these findings demonstrate that miR‑223‑3p drives microglial lactylation‑mediated M1 polarization through the FBXW7/Notch1/Hes1/SIRT1 signaling axis. The present study provides new insight into the role of lactylation in neuroinflammation and highlights miR‑223‑3p as a potential therapeutic target for AD.
Insights
MicroRNA-223-3p drives Alzheimer's disease neuroinflammation by promoting microglial M1 polarization and lactylation. This microRNA targets key signaling pathways, offering a potential therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Neuroinflammation is a key feature of Alzheimer's disease (AD).
- Microglial M1 polarization is closely associated with neuroinflammation in AD.
- Metabolic reprogramming in microglia plays a role in AD pathogenesis.
Purpose of the Study:
- To investigate the role of miR-223-3p in microglial metabolic reprogramming and neuroinflammation in AD.
- To elucidate the molecular mechanisms by which miR-223-3p influences microglial polarization.
- To identify miR-223-3p as a potential therapeutic target for AD.
Main Methods:
- Analysis of public datasets (GEO, ADNI) for miR-223-3p expression in AD.
- Overexpression and inhibition studies of miR-223-3p in microglia.
- Transcriptomic, metabolomic, and Seahorse analyses.
- Investigation of the FBXW7/Notch1/Hes1/SIRT1 signaling axis.
Main Results:
- miR-223-3p is upregulated in AD patients' brain, blood, and CSF.
- Overexpression of miR-223-3p promotes M1 polarization and increases reactive oxygen species (ROS).
- miR-223-3p enhances glycolysis, lactate production, and lactylation; inhibiting lactylation reduces M1 polarization and ROS.
- miR-223-3p suppresses SIRT1 and targets FBXW7, activating the Notch1/Hes1 pathway and further inhibiting SIRT1.
Conclusions:
- miR-223-3p promotes microglial lactylation-mediated M1 polarization via the FBXW7/Notch1/Hes1/SIRT1 axis.
- Lactylation plays a significant role in AD-associated neuroinflammation.
- miR-223-3p represents a promising therapeutic target for Alzheimer's disease.