ArticleProceedings of the National Academy of Sciences of the United States of America2023
Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Article
- A Multidimensional Engineering Strategy Reprograms Microglia via Targeted and Sustained-Release Extracellular Vesicles for Spinal Cord Injury Repair.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.Journal of neuroinflammation · 2026Article
- Inhibition of Microglial TRPV1 Ameliorates Brain Injury After Intracerebral Hemorrhage by Suppressing AMPK/PINK1-Mediated Mitophagy.CNS neuroscience & therapeutics · 2026Article
- Prussian blue analogue-mineralized ginseng-derived vesicles promote PPARγ nuclear translocation to suppress tumor vasculogenic mimicry and reverse the immunosuppressive microenvironment.Journal of nanobiotechnology · 2026Article
- Erk5-mediated microglial ferroptosis drives ischemic white matter damage via the Nfatc4-Clptm1l axis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?Frontiers in aging neuroscience · 2026Review
- Astragaloside's Role in Microglial Neuroinflammation: A Multi-Method Study Combining Experimental and Computational Analyses.Neurochemical research · 2025Article
- Lipid droplet accumulation in microglia and their potential roles.Lipids in health and disease · 2025Review
- APOE genotype determines cell-type-specific pathological landscape of Alzheimer's disease.Neuron · 2025Article
- Transcriptomic profiling identifies ferroptosis and NF-κB signaling involved in α-dimorphecolic acid regulation of microglial inflammation.Journal of translational medicine · 2025Article
- Engineering Dual Active Sites and Defect Structure in Nanozymes to Reprogram Jawbone Microenvironment for Osteoradionecrosis Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Linoleic acid drives pulmonary lymphoepithelioma-like carcinoma progression via PPAR-α/TF axis.Frontiers in oncology · 2025Article
- Ido2 Deficiency Exacerbates Motor Impairment and Reduces Aryl Hydrocarbon Receptor Activity through Decreased Kynurenine in a Chronic Demyelinating Mouse Model.Molecular neurobiology · 2025Article
- Macrophage exosomal miR-30c-2-3p in atherosclerotic plaques aggravates microglial neuroinflammation during large-artery atherosclerotic stroke via TGF-β/SMAD2 pathway.Journal of neuroinflammation · 2024Article
- Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder.Neuroscience bulletin · 2024Article
- MiR-223 enhances lipophagy by suppressing CTSB in microglia following lysolecithin-induced demyelination in mice.Lipids in health and disease · 2024Article
- Nervonic Acid Synthesis Substrates as Essential Components in Profiled Lipid Supplementation for More Effective Central Nervous System Regeneration.International journal of molecular sciences · 2024Review
- Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?CNS neuroscience & therapeutics · 2024Review
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.
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