Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
Mengqi Han, Bing Xie, Yuan Yu, Dan Xu, Yuan Shi, Meng Xu, Yuming Wu, Yujing Zhang, Xiaoyue Wen, Xin Wang, Zifan Zhen, Xinyu Zhang, Xueqiang Sun, Yin Yuan, You Shang, Shiying Yuan, Kenji Hashimoto, Jiancheng Zhang
Journal of Neuroinflammation December 18, 2025 DOI: 10.1186/s12974-025-03656-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study in mice Peer reviewed |
|---|---|
| Population | Mice (C57BL/6J and various transgenic lines) |
| Interventions | Chronic restraint stress fecal microbiota transplantation conditional CD8α deletion in γδ T cells hippocampal IL-17A overexpression rapamycin arketamine |
| Duration | 10-day chronic restraint stress period; behavioral tests and tissue collection performed after stress; specific intervention durations not stated |
| Topics | Depression Ketamine |
| Keywords | Chronic restraint stress Gut-brain axis Mitophagy Γδt cells |
| Key findings | Chronic stress drives gut-microbiota dysbiosis that promotes migration of small intestinal γδ T cells to the brain, where their IL-17A impairs hippocampal mitophagy and causes depression-like behavior; arketamine reverses this pathway. |
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.