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 Article has an altmetric score of 97

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 6

bHAf signaling regulates OL lineage maturation at the preOL stage via FoxO3.

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bHAf signaling regulates OL lineage maturation at the preOL stage via Fo...
(A) Elevated FoxO3 expression in chronic WMI in corpus callosum 4 days after H-I. Insets: The number of FoxO3-labeled cells (green; open arrowheads) is increased in WMI, but they do not colocalize with PDGFRα-labeled progenitors (red; filled arrowheads). (B) Nuclear localization of FoxO3 was detected 4 days after H-I in O4-labeled cells in WMI but not controls. (C) Rat slices treated 21 days with or without MDa HA (50 nM). MDa HA significantly increased Olig2+FoxO3+ cells in corpus callosum (white arrowheads) versus PBS controls. (D) Total Olig2+ and Olig2+FoxO3+ cells in the entire corpus callosum from rat slices treated 24 hours with or without bHAf (100 nM). (E) Primary mouse OPC cultures were cotransfected with the indicated constructs and mRFP (red) and induced to differentiate for 4 days with or without bHAf (500 nM). OPCs expressing FoxO3TM displayed a significant decrease in the total percentage of MBP-labeled OLs versus cells expressing FoxO3WT or control plasmids. (F and G) Molecular interactions among FoxO3, Brg1, and Olig2 in proliferating and differentiating OPCs and in response to bHAf (500 nM). ChIP assay defining Brg1 and Olig2 interactions with the FoxO3 promoter (F). ChIP assay defining FoxO3, Brg1, and Olig2 interactions with the MBP promoter (G). (H) Working model depicts that FoxO3 associates with SWI/SNF and Brg1 at the MBP promoter in proliferating OPCs but dissociates from the promoter (blue arrow) when pro-myelination signals induce OPC differentiation, consistent with FoxO3 repression of MBP transcription. When bHAf inactivates AKT and drives FoxO3 nuclear localization, SWI/SNF and Olig2 dissociate from the MBP promoter, blocking its transcription. A and B: n = 2 control and n = 3 H-I animals. C: n = 2 animals/condition from 2 litters; 6 slices total, 3 slices/condition/animal. D: n = 3 animals/condition; 3 litters; 9 slices total, 3 slices analyzed/condition/animal. E: n = 3 separate experiments and culture preparations. F and G: n = 2 separate experiments from separate culture preparations. *P < 0.05 by Student’s t test (E); **P < 0.001 by Student’s t test (D); mean SEM. Scale bars: 300 μm, A (insets: original magnification, ×40); 10 μm, B; 40 μm, C. Original magnification, ×20 (E).