Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice

Abstract

The number of young adult patients with major depression, one of the most common mental disorders, is gradually increasing in modern society. Stressful experiences in early life are considered one of the risk factors for chronic depressive symptoms, along with an abnormal inflammatory response in later life. Although increased inflammatory activity has been identified in patients with depression, the cause of long-lasting depressive states is still unclear. To identify the effects of cumulative mild stress in brain development periods, we generated a young adult depression mouse model exposed to cumulative mild stress (CPMS; cumulative mild prenatal stress, mild maternal separation, and mild social defeat) to mimic early life adversities. CPMS mice exhibited more long-lasting anxiety and depression-like behaviors than groups exposed to single or double combinations of mild stress in young adult age. Using the molecular works, we found that inflammatory cytokines, especially interleukin (IL)-17, upregulated microglial activation in the hippocampus, amygdala, and prefrontal cortex of CPMS mice. In the brains of CPMS mice, we also identified changes in the T helper (Th)-17 cell population as well as differentiation. Finally, anti-IL-17 treatment rescued anxiety and depression-like behavior in CPMS mice. In conclusion, we found that cumulative mild stress promoted long-lasting depressive symptoms in CPMS mice through the upregulation of IL-17. We suggest that the CPMS model may be useful to study young adult depression and expect that IL-17 may be an important therapeutic target for depression in young adults.

Sex Difference in Peripheral Inflammatory Biomarkers in Drug-Naïve Patients with Major Depression in Young Adulthood

“…In clinical studies, higher IL-17 levels were associated with anhedonia severity in men, but not in women [44,45]. Our results are also consistent with previous reports that the increase in IL-17 level, including Th17 cells, was associated with depressionlike behavior in rodent models [46,47]. Conversely, serum IL-1β, IL-6, and CRP levels significantly increased only in the female group with MDD compared with those in the ageand sex-matched controls.…”

Depression and Obesity in Patients With Psoriasis and Psoriatic Arthritis: Is IL-17-Mediated Immune Dysregulation the Connecting Link?

“…Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4+= and CD8+ T cells ( 60 ). Treatment of depressed mice with anti-IL-17 mAb inhibits glial differentiation and ameliorates anxiety and depression behaviors ( 61 ). In the human setting, CD4+CD25+ Tregs are found decreased in patients with major depression ( 62 ) ( Figure 1 ).…”

“…A hypothesis based on the assumption that microglia activation is pivotal for the increase of pro-inflammatory cytokines such as IL-16 and TGF-b, which polarize CD4+ T cells towards Th-17 is formulated. Experimental data suggest that anti-IL-17 mAb treatment, diminishes IL-17 induction and Th-17 differentiation and ameliorates anxiety and depression-like behaviors ( 61 ) (prepared with BioRender).…”

Electroacupuncture improves repeated social defeat stress-elicited social avoidance and anxiety-like behaviors by reducing Lipocalin-2 in the hippocampus

“…Recently, progressive multiple sclerosis model caused depression- and anxiety-like behaviors, which has been found simultaneously upregulation of IL-17 and GFAP in the hippocampus but not prefrontal cortex [ 45 ]. The recent study also reported that cumulative mild stress promoted depression-like behaviors in young adult mice and specifically upregulated IL-17 expression in the hippocampus [ 46 ]. We then further verified whether lipocalin 2 expression in RSDS was reduced by EA stimulation.…”