Chronic stress-induced depression-like behaviors through Th1-lymphocytes and microglia-mediated neuroinflammation in the mouse
Abstract
Recent studies showed the activation of T helper (Th) 1 and microglia during depression. However, the changes in peripheral and central lymphocyte subtypes, and their relationship with microglia in the depression are still unclear. To answer these questions, this study investigated concurrent alterations in lymphocyte subsets (Th1/Th2), microglial activation, and related neuroinflammation and neuronal changes in a mouse model of depression induced by chronic unpredictable mild stress (CUMS). Furthermore, pharmacological inhibitors targeting Th1 (STA-5326), M1 microglia (minocycline), or p38 MAPK (SB203580) were utilized to assess the contribution of these factors to behavioral and molecular outcomes.CUMS induced significant anhedonia and anxiety-like behaviors. These symptoms were accompanied by a decrease in central CD4 T cells and peripheral CD4/CD8 ratio, alongside an increased Th1/Th2 ratio. Hippocampal levels of cortisol, interleukin (IL)-2, IL-12, and the IFN-γ/IL-4 ratio were elevated. CUMS also activated microglia, P38-MAPK pathway and increased neuronal apoptotic signaling (reduced Bcl-2/Bax ratio), and decreased both 5-HT/5-HIAA ratio and neuroplasticity (PSD-95, DCX) in the hippocampus and prefrontal cortex. Notably, the correlations between microglia (Iba-1) and Th1 cell (IL-12), as well as both of them correlations with p-p38 were found. All these parameters were normalized by the three treatments. Interestingly, STA-5326 showed greater efficacy in restoring anhedonia and meningeal CD4 T cell levels, while SB203580 was most effective in normalizing 5-HT neurotransmitter.In summary, inhibiting Th1 lymphocyte activity, M1-microglia or p-38-MAPK pathways improved depression-like behaviors, which were associated with the normalization of peripheral and central immune imbalances, attenuation of neuroinflammation, and protection of neuroplasticity.
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BibTeX
@article{zhang2026chronic,
title = {{Chronic stress-induced depression-like behaviors through Th1-lymphocytes and microglia-mediated neuroinflammation in the mouse}},
author = {Cai Zhang and B Liu and Xiaohong Li and Thierry D Charlier and Kirthana Kunikullaya U and Harry W. M. Steinbusch and Cai Song},
journal = {European Journal of Pharmacology},
year = {2026},
month = sep,
doi = {10.1016/j.ejphar.2026.178710},
url = {https://hal.science/hal-05538788v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Chronic stress-induced depression-like behaviors through Th1-lymphocytes and microglia-mediated neuroinflammation in the mouse
AU - Cai Zhang
AU - B Liu
AU - Xiaohong Li
AU - Thierry D Charlier
AU - Kirthana Kunikullaya U
AU - Harry W. M. Steinbusch
AU - Cai Song
PY - 2026
DA - 2026/09/01
JO - European Journal of Pharmacology
DO - 10.1016/j.ejphar.2026.178710
UR - https://hal.science/hal-05538788v1
AB - Recent studies showed the activation of T helper (Th) 1 and microglia during depression. However, the changes in peripheral and central lymphocyte subtypes, and their relationship with microglia in the depression are still unclear. To answer these questions, this study investigated concurrent alterations in lymphocyte subsets (Th1/Th2), microglial activation, and related neuroinflammation and neuronal changes in a mouse model of depression induced by chronic unpredictable mild stress (CUMS). Furthermore, pharmacological inhibitors targeting Th1 (STA-5326), M1 microglia (minocycline), or p38 MAPK (SB203580) were utilized to assess the contribution of these factors to behavioral and molecular outcomes.CUMS induced significant anhedonia and anxiety-like behaviors. These symptoms were accompanied by a decrease in central CD4 T cells and peripheral CD4/CD8 ratio, alongside an increased Th1/Th2 ratio. Hippocampal levels of cortisol, interleukin (IL)-2, IL-12, and the IFN-γ/IL-4 ratio were elevated. CUMS also activated microglia, P38-MAPK pathway and increased neuronal apoptotic signaling (reduced Bcl-2/Bax ratio), and decreased both 5-HT/5-HIAA ratio and neuroplasticity (PSD-95, DCX) in the hippocampus and prefrontal cortex. Notably, the correlations between microglia (Iba-1) and Th1 cell (IL-12), as well as both of them correlations with p-p38 were found. All these parameters were normalized by the three treatments. Interestingly, STA-5326 showed greater efficacy in restoring anhedonia and meningeal CD4 T cell levels, while SB203580 was most effective in normalizing 5-HT neurotransmitter.In summary, inhibiting Th1 lymphocyte activity, M1-microglia or p-38-MAPK pathways improved depression-like behaviors, which were associated with the normalization of peripheral and central immune imbalances, attenuation of neuroinflammation, and protection of neuroplasticity.
SN - 1879-0712
SN - 0014-2999
ER -