Elsevier

Biological Psychiatry

Volume 73, Issue 7, 1 April 2013, Pages 622-630
Biological Psychiatry

Archival Report
Inflammatory T Helper 17 Cells Promote Depression-like Behavior in Mice

https://doi.org/10.1016/j.biopsych.2012.09.021Get rights and content

Background

Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact central nervous system functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models, Th17 cells promote susceptibility to depression-like behaviors.

Methods

Behavioral characteristics were measured in male mice administered Th17 cells, CD4+ cells, or vehicle and in retinoid-related orphan receptor-γT (RORγT)+/GFP mice or male mice treated with RORγT inhibitor or anti-interleukin-17A antibodies.

Results

Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the RORγT transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of RORγT as a potential intervention. Treatment with the RORγT inhibitor SR1001, or anti-interleukin-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness.

Conclusions

These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells.

Section snippets

Mice and Behavioral Assessments

C57BL/6 and C57BL/6-129 Rorc(γT)+/GFP (6–12 weeks) male mice were from the Jackson Laboratories (Bar Harbor, Maine) and GSK3S21A/S21A/S9A/S9A knockin mice were from Dr. Dario Alessi (University of Dundee, United Kingdom). Six-week-old mice were used to prepare T cells, while 8- to 12-week-old mice were used for behavioral assessments. The Rorc(γT)+/GFP mice were obtained by crossing Rorc(γT)+/GFP×Rorc(γT)+/GFP to produce 50% Rorc(γT)+/GFP, 25% wild-type, and 25% Rorc(γT)GFP/GFP mice and

Results

Stress is a critical factor in promoting susceptibility to depression 2, 38 and is modeled in rodents with the learned helplessness paradigm of depression-like behavior (39) to assess modulators of mood, while limitations of animal models are also well recognized 38, 40, 41. The traditional learned helplessness paradigm involves stressing mice with mild, unpredictable, and inescapable footshocks (IES) and typically 24 hours later exposing mice to mild footshocks from which they are free to

Discussion

The growing evidence of causative links between inflammation and depression 3, 4 indicates that targets of inflammatory molecules contribute to establishing a prodepressant environment. This study focused on T cells because they are major sensors of the cytokine environment, each subtype of T helper CD4+ cell responds to a different cytokine signature, and, importantly, T cells are more enduring than transiently expressed cytokines, potentially enabling T cells to contribute to the prolonged

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