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. 2018 Dec;43(13):2597-2605.
doi: 10.1038/s41386-018-0154-1. Epub 2018 Jul 16.

Resolution of Inflammation-Induced Depression Requires T Lymphocytes and Endogenous Brain interleukin-10 Signaling

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Free PMC article

Resolution of Inflammation-Induced Depression Requires T Lymphocytes and Endogenous Brain interleukin-10 Signaling

Geoffroy Laumet et al. Neuropsychopharmacology. .
Free PMC article

Abstract

In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior. Duration of depression-like behavior was markedly prolonged in mice without mature T or B lymphocytes (Rag1-/- mice). This prolonged depression-like behavior was associated with persistent upregulation of the tryptophan-metabolizing enzyme indoleamine-2,3-dioxygenase (Ido)1 in the prefrontal cortex (PFC). Reconstitution of Rag1-/- mice with T lymphocytes normalized resolution of depression-like behavior and expression of Ido1 in the PFC. During resolution of inflammation-induced depression-like behavior, T lymphocytes accumulated in the meninges and were required for induction of interleukin (IL)-10 in the meninges and the PFC. Inhibition of IL-10 signaling by nasal administration of neutralizing anti-IL-10 antibody to WT mice led to persistent upregulation of Ido1 in the PFC and prolonged depression-like behavior. Conversely, nasal administration of recombinant IL-10 in Rag1-/- mice normalized Ido1 expression and resolution of depression-like behavior. In conclusion, the present data show for the first time that resolution of inflammation-induced depression is an active process requiring T lymphocytes acting via an IL-10-dependent pathway to decrease Ido1 expression in the brain. We propose that targeting the T lymphocyte/IL-10 resolution pathway could represent a novel approach to promote recovery from major depressive disorder.

Conflict of interest statement

RD has received honorarium from Danone Nutricia Research France. The other authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
T lymphocytes are necessary for resolution of lipopolysaccharide (LPS)-induced depression-like behavior. a The forced-swim test (FST) was performed in wild-type (WT) and Rag1−/− mice (n = 6 mice/group) 24 h and 72 h after injection of phosphate-buffered saline (PBS) or LPS. Two-way ANOVA followed by Bonferroni’s multiple correction test (treatment effect F(3,40) = 9.31, P < 0.0001). b FST was performed in Rag1−/− and reconstituted Rag1−/− mice (n = 8 mice/group) 24 h and 72 h after injection of LPS. Two-way ANOVA followed by Bonferroni’s correction (time × treatment interaction F(3,56) = 4.09, P = 0.011). c The tail-suspension test (TST) was performed in WT and Rag1−/− mice at 24 h post-injection (n = 7 mice/group). Two-way ANOVA followed by Bonferroni’s correction (LPS effect F(1,24) = 45.1, P = 0.0001). d TST in WT, Rag1−/− and reconstituted Rag1−/− mice (n = 6 mice/group) at 72 h after injection of LPS. One-way ANOVA followed by Bonferroni’s correction (F(4,25) = 6.49, P = 0.001). e Body weight, (f) food intake, and (g) spontaneous locomotor activity were monitored after injection of PBS or LPS (n = 8 mice/group). The data are presented as mean ± standard error of the mean. **P < 0.01, *P < 0.05
Fig. 2
Fig. 2
T lymphocytes regulate Il10 and Ido1 expression in the prefrontal cortex (PFC). a Ido1 mRNA level in the PFC 72 h after injection of lipopolysaccharide (LPS) (n = 6 mice per group). One-way ANOVA followed by Bonferroni’s multiple correction test (F(4,25) = 5.02, P = 0.004). b Ido1 mRNA level in the PFC 24 h after injection of LPS (n = 6–7 mice per group). Two-way ANOVA followed by Bonferroni’s multiple correction test (genotype x LPS interaction F(1,22) = 0.02, p = 0.89). mRNA levels of glial cell markers and proinflammatory cytokines in the PFC 24 h (c) and 72 h (d) post-LPS (n = 6–8 mice per group). e Il10 mRNA level in the PFC 72 h after injection in WT, Rag1−/− and reconstituted Rag1−/− mice (n = 8 mice/group). One-way ANOVA followed by Bonferroni’s multiple correction test (F(5,42) = 6.86, P = 0.0001). f Il10 mRNA level in the PFC 24 h after injection in WT and Rag1−/− mice (n = 7 mice/group). Two-way ANOVA followed by Bonferroni’s multiple correction test (genotype × LPS interaction F(1,21) = 0.06, p = 0.81). g Anti-inflammatory cytokine expression in the PFC 72 h post-LPS (n = 6–8 mice/group). Data are normalized to expression levels in the PBS group. The gene Aif1 encodes IBA1. The data are presented as mean ± standard error of the mean. ***P < 0.001, **P < 0.01, *P < 0.05
Fig. 3
Fig. 3
T lymphocytes transiently accumulate in the meninges prior resolution of depression-like behavior. a Cd3 mRNA level in the prefrontal cortex (PFC) 24 h and 72 h after lipopolysaccharide (LPS) injection in wild-type (WT) mice (n = 8 mice/group). b Cd3 mRNA level in the hippocampus 24 h and 72 h after (c) Cd3 mRNA level in the meninges 24 h and 72 h post-LPS in WT mice (n = 6 mice/group). Two-way ANOVA followed by Bonferroni’s correction (time × treatment interaction F(1,10) = 24.1, P = 0.0006). d Representative images of the whole mounted meninges (×4) stained with DAPI and anti-CD3 (green) 24 h after PBS or LPS. e Representative images of higher magnification (×10) of the central sinus of the meninges indicated by a square in the previous panel. f Quantification of the CD3+ T lymphocytes in the 3 sinus of the meninges 24 h after LPS (n = 4 mice/group). T test (df = 6, p = 0.03). The data are presented as mean ± standard error of the mean. ***P < 0.001, **P < 0.01, *P < 0.05
Fig. 4
Fig. 4
T lymphocytes are not the source of IL-10 to induce resolution. a Il10 mRNA level in the meninges 72 h post-LPS (n = 6 mice per group). One-way ANOVA followed by Bonferroni’s correction (F(4,20) = 9.76, P = 0.0002). b The forced-swim test was performed 24 h and 72 h post-injection in Rag1−/− mice reconstituted with WT or Il10−/− T lymphocytes (n = 5 mice/group). Two-way ANOVA followed by Bonferroni’s correction (T lymphocytes genotype × time interaction, F(3,32) = 5.26, P = 0.005). c Ido1 mRNA level in the PFC 72 h post-LPS in Rag1−/− mice reconstituted with WT or Il10−/− T lymphocytes (n = 5 mice/group). d Il10 mRNA level in the PFC 72 h post-LPS in Rag1−/− mice reconstituted with WT or Il10−/− T lymphocytes (n = 5 mice/group). Two-way ANOVA followed by Bonferroni’s correction (LPS effect, F(1,16) = 9.75, P = 0.007). The data are presented as mean ± standard error of the mean. Significant effects of LPS are shown by * for Rag1−/− mice reconstituted with WT and # for Il10−/− T lymphocytes; ***P < 0.001, **P < 0.01, */#P < 0.05
Fig. 5
Fig. 5
Interleukin (IL)-10 signaling is necessary and sufficient to downregulate Ido1 expression and for resolution of LPS-induced depression-like behavior. (a) Il10 mRNA level in the prefrontal cortex (PFC) and the meninges 24 h post-LPS (n = 6 mice per group). Two-way ANOVA followed by Bonferroni’s correction (tissue × treatment interaction, F(1,17) = 51.5, P < 0.0001). b The FST was performed 24 h and 72 h post-injection in WT mice after nasal administration of neutralizing anti–IL-10 antibody or immunoglobulin (Ig)G (n = 7 mice/group). Two-way ANOVA followed by Bonferroni’s correction (treatment, F(2,18) = 7.52, P = 0.004). c The TST was performed at 72 h post-LPS after nasal administration of anti-IL-10 (n = 7 mice per group). One-way ANOVA followed by Bonferroni’s correction (F(2, 18) = 6.42, P = 0.008). d Il10 and Ido1 mRNA levels in the PFC 72 h post-LPS in WT mice after nasal administration of anti–IL-10 antibody or IgG (n = 7 mice per group). Two-way ANOVA followed by Bonferroni’s correction (tissue × treatment interaction, F(2,18) = 4.75, P = 0.02). e Ido1 mRNA level in BV2 cells 6 h after treatment with recombinant interferon (rIFN)-γ in the presence or absence of recombinant interleukin (IL)-10 fusion protein (n = 5 per group). One-way ANOVA followed by Bonferroni’s correction (F(2, 12) = 20.8, P = 0.0001). f FST was performed 24 h and 72 h post-injection in Rag1−/− mice (n = 7 mice per group) after nasal injection of recombinant IL-10 or PBS. Two-way ANOVA followed by Bonferroni’s correction (treatment, F(2,18) = 28.5, P < 0.0001). g Ido1 mRNA levels in the PFC of Rag1−/− mice 72 h post-LPS after nasal injection of recombinant IL-10 (n = 7 mice/group). One-way ANOVA followed by Bonferroni’s correction (F(2, 15) = 14.6, P = 0.0003). The data are presented as mean ± standard error of the mean. ***P < 0.001, **P < 0.01, *P < 0.05

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