2. Academic Validation
  3. Peripheral cytokine dysregulation, microglial dysfunction in adolescent major depressive disorder: Neuroimmune crosstalk implications

Peripheral cytokine dysregulation, microglial dysfunction in adolescent major depressive disorder: Neuroimmune crosstalk implications

  • Psychoneuroendocrinology. 2025 Oct 17:183:107656. doi: 10.1016/j.psyneuen.2025.107656.
Xiaoshuang Shen 1,  Wenbo Ji 2,  Hongyu Zheng 1,  Biao Yu 2,  Ying Wan 2,  Heping Cai 2,  Haiming Dai 3,  Hui Zhong 4
Affiliations

Affiliations

  • 1 Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Child and Adolescents, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China.
  • 2 Department of Clinical Pharmacy, Anhui Provincial Children's Hospital, Hefei, Anhui 230000, China.
  • 3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: dai.haiming@mayo.edu.
  • 4 Affiliated Psychological Hospital of Anhui Medical University, Hefei, Anhui 230000, China; Department of Child and Adolescents, Hefei Fourth People's Hospital, Hefei, Anhui 230000, China. Electronic address: 313956777@qq.com.
PMID: 41138684 DOI: 10.1016/j.psyneuen.2025.107656
Abstract

Background: Major depressive disorder (MDD) exhibits a high prevalence among adolescents; however, its pathogenesis remains unclear. This study aimed to investigate the relationship between cytokine dysregulation and microglial dysfunction in adolescents with MDD (regardless of disease onset or duration) during the course of the disorder.

Methods: This study included 60 adolescent patients with MDD and 25 healthy controls (HCs). Peripheral blood levels of nine target cytokines-including interleukins (IL-1α, IL-1β, IL-6, IL-17A, IL-18), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF)-were measured using ultrasensitive multiplex electrochemiluminescence assays. To better understand the potential changes in microglial cells of adolescents with MDD, the human microglial cell line HMC3 was treated with 3-hydroxykynurenine (3-HK), a key neurotoxic metabolite of the kynurenine pathway (KP), and the effects of 3-HK on microglial cells were subsequently evaluated.

Results: After multiple test correction using the Holm method, compared with the HCs, adolescents with MDD exhibited a significant increase in the level of the peripheral pro-inflammatory cytokine IL-1α. Moreover, the levels of IL-1β, IL-6, IL-17A, and IL-18 showed an upward trend, while the levels of TNF-α and IFN-γ showed a downward trend, yet none of these trends reached statistical significance. In addition, G-CSF levels were significantly decreased, while M-CSF levels were significantly increased. In vitro experiments, 3-HK significantly reduced the viability of human microglial cells. Further experiments demonstrated that 3-HK induced microglial Pyroptosis in a concentration-dependent manner via the mitochondrial pathway, leading to the release of the pro-inflammatory cytokine IL-1β.

Conclusion: Dysregulation of cytokines may lead to excessive activation of microglia, resulting in increased release of the neurotoxic KP metabolite 3-HK. This suppresses microglial proliferation and induces microglial cell death, including Pyroptosis, accompanied by the release of pro-inflammatory cytokines.

Keywords

3-hydroxykynurenine; Adolescents; Cytokine; Major depressive disorder; Microglia; Pyroptosis.

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