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

Authors

Taasin Srivastava, Oregon Health and Science University
Parham Diba, Oregon Health and Science University
Justin M. Dean, Oregon Health and Science University
Fatima Banine, Oregon National Primate Research Center
Daniel Shaver, Oregon Health and Science University
Matthew Hagen, Oregon Health and Science University
Xi Gong, Oregon Health and Science University
Weiping Su, Oregon National Research Center
Ben Emery, Oregon Health and Science University
Daniel L. Marks, Oregon Health and Science University
Edward N. Harris, University of Nebraska - LincolnFollow
Bruce Baggentoss, University of Oklahoma Health Sciences Center
Paul H. Weigel, University of Oklahoma Health Sciences Center
Larry S. Sherman, Oregon Health and Science University
Stephen A. Back, Oregon Health and Science University

Date of this Version

2018

Citation

J Clin Invest. 2018;128(5):2025–2041.

Comments

https://doi.org/10.1172/JCI94158.

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.