Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 622-630 |
| Number of pages | 9 |
| Journal | Biological Psychiatry |
| Volume | 73 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2013 |
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Keywords
- Antidepressant
- depression
- learned helplessness
- neural-immune interactions
- RORγT
- Th17 cells
ASJC Scopus subject areas
- Biological Psychiatry
Cite this
Inflammatory T helper 17 cells promote depression-like behavior in mice. / Beurel, Eleonore; Harrington, Laurie E.; Jope, Richard S.
In: Biological Psychiatry, Vol. 73, No. 7, 01.04.2013, p. 622-630.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inflammatory T helper 17 cells promote depression-like behavior in mice
AU - Beurel, Eleonore
AU - Harrington, Laurie E.
AU - Jope, Richard S
PY - 2013/4/1
Y1 - 2013/4/1
N2 - 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.
AB - 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.
KW - Antidepressant
KW - depression
KW - learned helplessness
KW - neural-immune interactions
KW - RORγT
KW - Th17 cells
UR - http://www.scopus.com/inward/record.url?scp=84875213291&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875213291&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2012.09.021
DO - 10.1016/j.biopsych.2012.09.021
M3 - Article
C2 - 23174342
AN - SCOPUS:84875213291
VL - 73
SP - 622
EP - 630
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 7
ER -