A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors
Taasin Srivastava, … , Larry S. Sherman, Stephen A. Back
Taasin Srivastava, … , Larry S. Sherman, Stephen A. Back
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2025-2041. https://doi.org/10.1172/JCI94158.
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Research Article Inflammation Neuroscience

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.

Authors

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

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Figure 1

Neonatal rat H-I WM lesions deplete MDa HA.

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Neonatal rat H-I WM lesions deplete MDa HA. (A) Schematic diagram of the...
(A) Schematic diagram of the H-I strategy and postnatal ages for tissue analysis. (B and C) Representative images of the supracallosal WM of the corpus callosum (CC) and overlying cortex (Ctx) in control and H-I samples at P4 (B) and P14 (C) stained for GFAP and HABP. Diffuse reduction in MDa HA persisted until P14 (C). (D) Recovery of total HA from WM lesions after H-I. Comparison of true controls (Control), hypoxic controls (Hypoxia only), and H-I group (Lesion) versus contralateral hypoxic hemisphere (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C).