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 3

bHAf regulates AKT in a tolerance-like manner.

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bHAf regulates AKT in a tolerance-like manner. (A–C) bHAf induces persis...
(A–C) bHAf induces persistent AKT dephosphorylation in rat slices treated with bHAf (100 nM). Representative blots and quantification after probing with pAKT-S473, pAKT-T308, pERK1/2, AKT (total AKT), and actin antibodies. Note the transient increase in AKT phosphorylation followed by persistent reduction to control levels at 4 hours (A), 24 hours (B), and 5 or 9 days (C). (D) BDNF (50 ng/ml) induces persistent AKT phosphorylation at 30 minutes, and 4 or 24 hours. (E) Experimental design to determine whether BDNF can overcome bHAf-mediated AKT desensitization (left); and representative blots (right). (F) Chronic WMI leads to persistent AKT dephosphorylation that normalizes with delayed partial myelination. Representative blots and quantification from 3 rats that underwent H-I at P3 versus control (C), comparing AKT phosphorylation in lesion hemisphere at P4, P7, P10, P14, and P21. Actin was the loading control. (G) Progressive recovery of myelination following WMI. Representative images depicting MBP staining at P10, P14, and P21 (asterisks indicate H-I hemisphere). A–E: n = 3 independent studies from 3 separate litters; 2 slices/condition. F: n = 3 animals (control) and n = 6 animals (H-I). G: n = 9 animals/condition. *P < 0.05 by Student’s t test; mean ± SEM. Scale bars: 600 μm, G.