Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine

J Neuroinflammation. 2025 Dec 18;23(1):24. doi: 10.1186/s12974-025-03656-4.

Abstract

Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays (open-field, sucrose-preference, tail-suspension, forced-swim), 16S rRNA profiling, fecal microbiota transplantation, Kaede photoconversion, conditional CD8α deletion in γδ T cells, hippocampal IL-17A overexpression, rapamycin treatment, and administration of the antidepressant arketamine. CRS increased gut and brain permeability, induced gut-microbiota dysbiosis, and promoted migration of small intestinal CD8α⁺ γδ T17 cells to the meninges and brain; γδ T cells were the predominant IL-17A source in the brain. Kaede tracing confirmed an intestinal origin, and CRS-associated microbiota alone transferred γδ T cell trafficking and depression-like behavior to recipients. In the hippocampus, CRS elevated IL-17A and impaired PINK1/Parkin-mediated mitophagy (decreased PINK1, Parkin, Beclin-1, and LC3B-II/I; increased p62), reduced ATP, and produced mitochondrial and synaptic ultrastructural deficits. IL-17A overexpression further worsened mitophagy and behavior, whereas rapamycin restored both. Conditional deletion of CD8α in γδ T cells reduced brain γδ T17 infiltration, lowered hippocampal IL-17A, rescued mitophagy and synapses, and improved behavior. Arketamine normalized dysbiosis and barrier markers, curtailed γδ T cell trafficking, decreased hippocampal IL-17A, restored mitophagy, and alleviated depression-like behavior in both sexes. These findings delineate a stress-responsive microbiota-γδ T cell-IL-17A pathway that compromises hippocampal mitophagy and identify arketamine as a candidate modulator of this axis, nominating mitophagy and γδ T cell trafficking as translational targets.

Keywords: Chronic restraint stress; Depression; Gut-brain axis; Ketamine; Mitophagy; γδT cells.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Depression* / drug therapy
  • Depression* / etiology
  • Depression* / metabolism
  • Gastrointestinal Microbiome / drug effects
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Interleukin-17* / metabolism
  • Intraepithelial Lymphocytes* / drug effects
  • Intraepithelial Lymphocytes* / metabolism
  • Ketamine* / analogs & derivatives
  • Ketamine* / pharmacology
  • Ketamine* / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitophagy* / drug effects
  • Mitophagy* / physiology
  • Receptors, Antigen, T-Cell, gamma-delta* / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stress, Psychological* / complications
  • Stress, Psychological* / metabolism

Substances

  • Ketamine
  • Interleukin-17
  • Il17a protein, mouse
  • Receptors, Antigen, T-Cell, gamma-delta
  • Antidepressive Agents