Stress-induced gut immune signaling through intestinal γδ T17 cells and IL-17A disrupted hippocampal in mice and was reversed by arketamine.
Evidence
A mouse chronic restraint stress study combined behavior tests, microbiome profiling, fecal microbiota transplantation, cell tracing, conditional γδ T-cell CD8α deletion, IL-17A overexpression, rapamycin, and arketamine treatment.
Caveat
The findings come from stress-induced mouse models and mechanistic interventions, so translation to human depression and arketamine treatment remains untested here.
Simplified
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 (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.
Key numbers
3 of 4
Increase in γδ T cell trafficking
3 of 4 mice showed increased γδ T cell migration to the brain after CRS.
10 mg/kg
Arketamine dosage
Arketamine was administered at a dosage of 10 mg/kg prior to CRS.
28 days
CRS-induced depression-like behaviors
Mice underwent CRS for 28 consecutive days to evaluate behavioral outcomes.
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