ArticleThe Journal of clinical investigation2018
A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- From oxidative stress to epigenetic regulation: Molecular mechanisms of preterm brain injury and neuroprotective strategies (Review).Molecular medicine reports · 2026Review
- CD44 as a Conserved Biomarker and Functional Modulator of Neuroinflammation in Multiple Sclerosis and Beyond.Molecular neurobiology · 2026Article
- FOXO family and neurodegenerative diseases: Mechanisms of action and therapeutic potential.Redox biology · 2026Review
- Shared genetic architecture between the topology of brain white matter structural connectome and fluid intelligence.Communications biology · 2026Article
- The Molecular Neurobiology of NG2-Expressing Glial Cells in Cerebral Small Vessel Disease Pathogenesis.Molecular neurobiology · 2026Review
- The future of Forkhead box O transcription factors.The Biochemical journal · 2026Review
- Hyaluronidases as Targets for the Treatment of Neurological Diseases.Proteoglycan research · 2025Article
- The Future of PET Imaging in Multiple Sclerosis: Characterisation of Individual White Matter Lesions.Journal of clinical medicine · 2025Review
- The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation.ASN neuro · 2025Article
- Distinct chemical structures inhibit the CEMIP hyaluronidase and promote oligodendrocyte progenitor cell maturation.The Journal of biological chemistry · 2024Article
- Potential Role of Endoplasmic Reticulum Stress in Modulating Protein Homeostasis in Oligodendrocytes to Improve White Matter Injury in Preterm Infants.Molecular neurobiology · 2024Review
- TSG-6-Mediated Extracellular Matrix Modifications Regulate Hypoxic-Ischemic Brain Injury.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing.Translational neurodegeneration · 2024Review
- Ferroptosis of Microglia in Aging Human White Matter Injury.Annals of neurology · 2023Article
- Postischemic Infusion of Apigenin Reduces Seizure Burden in Preterm Fetal Sheep.International journal of molecular sciences · 2023Article
- Roles of NG2 Glia in Cerebral Small Vessel Disease.Neuroscience bulletin · 2023Review
- Genetic architecture of the white matter connectome of the human brain.Science advances · 2023Article
- Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review.Journal of the neurological sciences · 2022Article
- New insights into the immunologic role of oligodendrocyte lineage cells in demyelination diseases.Journal of biomedical research · 2022Article
- Shh and Olig2 sequentially regulate oligodendrocyte differentiation from hiPSCs for the treatment of ischemic stroke.Theranostics · 2022Article
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 1 country.
Funding
Abstract
Cerebral white matter injury (WMI) persistently disrupts myelin regeneration by oligodendrocyte progenitor cells (OPCs). We identified a specific bioactive hyaluronan fragment (bHAf) that downregulates myelin gene expression and chronically blocks OPC maturation and myelination via a tolerance-like mechanism that dysregulates pro-myelination signaling via AKT. Desensitization of AKT occurs via TLR4 but not TLR2 or CD44. OPC differentiation was selectively blocked by bHAf in a maturation-dependent fashion at the late OPC (preOL) stage by a noncanonical TLR4/TRIF pathway that induced persistent activation of the FoxO3 transcription factor downstream of AKT. Activated FoxO3 selectively localized to oligodendrocyte lineage cells in white matter lesions from human preterm neonates and adults with multiple sclerosis. FoxO3 constraint of OPC maturation was bHAf dependent, and involved interactions at the FoxO3 and MBP promoters with the chromatin remodeling factor Brg1 and the transcription factor Olig2, which regulate OPC differentiation. WMI has adapted an immune tolerance-like mechanism whereby persistent engagement of TLR4 by bHAf promotes an OPC niche at the expense of myelination by engaging a FoxO3 signaling pathway that chronically constrains OPC differentiation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.