Th17 cell mediated oligodendrocyte precursor cell arrest drives hippocampal demyelination in diabetic cognitive dysfunction

  • Clin Sci (Lond). 2026 Mar 6:CS20257295. doi: 10.1042/CS20257295.
Jia-Wei Hu  1  2 ,  Hong-Dan Yu  1  2 ,  Sheng-Xue Yu  1  2 ,  Wen-Qiang Liu  1  2 ,  Yu-Fei Wang  1  2 ,  Ya-Li Wang  1  2 ,  Xin-Yuan Chen  1  2 ,  Quan-Ling Miao  1  2 ,  Yi-Rong Yuan  1  2 ,  Wei Dai  1  2 ,  Meng-Ren Liu  1  2 ,  Na Zhang  1  2 ,  Jia-Heng Sui  1  2 ,  Xue-Zheng Liu  1  2 ,  Wei Shan  1 ,  Zhong-Fu Zuo  1  2
Affiliations
  • 1. Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China.
  • 2. Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, 121001, PR China.
PMID: 41797721 DOI: 10.1042/CS20257295
Abstract

Demyelination is pivotal in diabetic cognitive dysfunction (DCD), with Th17 cells gaining attention, yet their hippocampal infiltration and mechanisms in diabetes remain unelucidated. Using streptozotocin (STZ)-induced diabetic mice, we demonstrated Th17 cell infiltration and elevated IL-17A in the hippocampus via CD4/IL-17A immunofluorescence and Western blot. Administering IL-17A neutralizing antibodies (NAbs) improved cognitive performance (Morris water maze: reduced escape latency, increased platform crossings/target quadrant time), attenuated neuroinflammation (reduced IL-17A, TNF-α, IL-1β, IL-6; increased IL-10, IL-4; decreased microglial activation/IBA-1), restored blood-brain barrier integrity (increased ZO-1, Occludin), and promoted remyelination (increased MBP, CNPase; decreased NG2, olig2; Luxol fast blue). IL-17A NAbs also enhanced phosphorylated ERK1/2 (p-ERK). Crucially, co-treatment with the ERK Inhibitor PD98059 partially reversed the protective effects of IL-17A NAbs on these parameters. These findings indicate that IL-17A, secreted by infiltrating Th17 cells, exacerbates hippocampal demyelination in DCD by inhibiting oligodendrocyte precursor cell (OPC) maturation via suppression of the ERK1/2 pathway and concurrently activating microglia to amplify neuroinflammation, ultimately driving cognitive impairment.

Keywords
Diabetic cognitive dysfunction; ERK1/2; IL-17A; demyelination; oligodendrocyte precursor cell.
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