A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors
| Autor: | Fatima Banine, Stephen A. Back, Ben Emery, Daniel Shaver, Bruce A. Baggenstoss, Xi Gong, Taasin Srivastava, Matthew W. Hagen, Weiping Su, Edward N. Harris, Daniel L. Marks, Paul H. Weigel, Parham Diba, Justin M. Dean, Larry S. Sherman |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Oligodendrocyte Transcription Factor 2 Neuregulin-1 Biology OLIG2 Rats Sprague-Dawley 03 medical and health sciences Myelin Mice 0302 clinical medicine medicine Immune Tolerance Animals Humans Protein kinase B Transcription factor Mice Knockout Oligodendrocyte Precursor Cells Forkhead Box Protein O3 Toll-Like Receptors DNA Helicases Nuclear Proteins General Medicine Oligodendrocyte Cell biology Rats stomatognathic diseases 030104 developmental biology medicine.anatomical_structure nervous system FOXO3 Female Signal transduction Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Research Article Signal Transduction Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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