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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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 5

bHAf signals via TRIF to regulate AKT.

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bHAf signals via TRIF to regulate AKT. (A) Strategy to define roles for ...
(A) Strategy to define roles for MyD88 and TRIF in myelination failure. (B) OPC maturation was blocked in MyD88–/– murine slices treated with MDa HA (50 nM) or bHAf (100 nM). (C) TRIF–/– slices treated with MDa or bHAf did not differ from those treated with vehicle (PBS). (D and E) bHAf-induced AKT phosphorylation (pAKT-S473) is TRIF and TLR4 dependent. Representative blots and quantification from studies with TRIF–/– (D) or TLR4–/– (E) animals. (F) β-Arrestin2 (Arrb2) is rapidly recruited to the TRIF-TRAF6 complex following bHAf treatment. Lysates were prepared from rat slices treated with or without bHAf (100 nM) at the indicated times and analyzed by IP using TRAF6 antibody. Representative blots were probed with TRIF, TRAF6, and β-arrestin2 antibodies: IP (upper panel); total cell lysate (lower panel). B and C: n = 3–4 mice (P3/P4) per condition for each genotype from separate litters; 3 slices/animal/treatment condition; 9–12 slices total. D and E: n = 2 mice (P3/P4) per condition for each genotype from separate litters; 2 slices/animal/treatment condition. F: n = 2 experiments from 2 separate litters; 2 slices/condition. *P < 0.05 by ANOVA; **P < 0.001 by ANOVA; mean ± SD (B and C) and mean ± SEM (D and E).