@article{20046544ab484f839db2b5c1ec726734,
title = "A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors",
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.",
author = "Taasin Srivastava and Parham Diba and Dean, {Justin M.} and Fatima Banine and Daniel Shaver and Matthew Hagen and Xi Gong and Weiping Su and Ben Emery and Marks, {Daniel L.} and Harris, {Edward N.} and Bruce Baggenstoss and Weigel, {Paul H.} and Sherman, {Larry S.} and Back, {Stephen A.}",
note = "Funding Information: This work was supported by the National Institute of Neurological Disorders and Stroke (NS054044; NS045737 to SAB), the National Institute on Aging (AG-31892 to SAB and LSS), an NIH Directors award for the operation of the Oregon National Primate Research Center (P51OD01109), the American Stroke Association (grant-in-aid 11GRNT7510072 to SAB), the Congressionally Directed Medical Research Programs (MS160144 to LSS), and the National Multiple Sclerosis Society (RG 4843A5/1 to LSS). We are grateful to Susan Aic-her and the OHSU EM core for ultrastructural studies supported by NIH grant P30NS061800. We are grateful to Mary Stenzel-Poore, Susan Stevens, and Dale Fortin for their invaluable discussions regarding mechanisms of IT and signaling and to Marjorie Grafe for valuable advice and review of human neuropathology specimens. TS was supported by a Huebner Family Postdoctoral Fellowship. Publisher Copyright: {\textcopyright} 2018 Academic Press. All rights reserved.",
year = "2018",
month = may,
day = "1",
doi = "10.1172/JCI94158",
language = "English (US)",
volume = "128",
pages = "2025--2041",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",
}