A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors

Taasin Srivastava, Parham Diba, Justin M. Dean, Fatima Banine, Daniel Shaver, Matthew Hagen, Xi Gong, Weiping Su, Ben Emery, Daniel L. Marks, Edward N Harris, Bruce Baggenstoss, Paul H. Weigel, Larry S. Sherman, Stephen A. Back

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2025-2041
Number of pages17
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
StatePublished - May 1 2018

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Immune Tolerance
Oligodendroglia
Stem Cells
Hyaluronic Acid
Cell Differentiation
Myelin Sheath
Transcription Factors
Chromatin Assembly and Disassembly
Wounds and Injuries
Multiple Sclerosis
Regeneration
Down-Regulation
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Srivastava, T., Diba, P., Dean, J. M., Banine, F., Shaver, D., Hagen, M., ... Back, S. A. (2018). A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. Journal of Clinical Investigation, 128(5), 2025-2041. https://doi.org/10.1172/JCI94158

A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. / Srivastava, Taasin; Diba, Parham; Dean, Justin M.; Banine, Fatima; Shaver, Daniel; Hagen, Matthew; Gong, Xi; Su, Weiping; Emery, Ben; Marks, Daniel L.; Harris, Edward N; Baggenstoss, Bruce; Weigel, Paul H.; Sherman, Larry S.; Back, Stephen A.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 2025-2041.

Research output: Contribution to journalArticle

Srivastava, T, Diba, P, Dean, JM, Banine, F, Shaver, D, Hagen, M, Gong, X, Su, W, Emery, B, Marks, DL, Harris, EN, Baggenstoss, B, Weigel, PH, Sherman, LS & Back, SA 2018, 'A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors', Journal of Clinical Investigation, vol. 128, no. 5, pp. 2025-2041. https://doi.org/10.1172/JCI94158
Srivastava, Taasin ; Diba, Parham ; Dean, Justin M. ; Banine, Fatima ; Shaver, Daniel ; Hagen, Matthew ; Gong, Xi ; Su, Weiping ; Emery, Ben ; Marks, Daniel L. ; Harris, Edward N ; Baggenstoss, Bruce ; Weigel, Paul H. ; Sherman, Larry S. ; Back, Stephen A. / A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 2025-2041.
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