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Updated: Jun 24, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated
Yuan Li1,2, Bing Zhan1, Xiao Zhuang1
1Key Laboratory of Infection and Immunity, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44# Wenhua Xi Road, Jinan, 250012, Shandong, China.
Abstract:
The dysregulation of pro- and anti-inflammatory processes in the brain has been linked to the pathogenesis of major depressive disorder (MDD), although the precise mechanisms remain unclear. In this study, we discovered that microglial conditional knockout of Pdcd4 conferred protection against LPS-induced hyperactivation of microglia and depressive-like behavior in mice. Mechanically, microglial Pdcd4 plays a role in promoting neuroinflammatory responses triggered by LPS by inhibiting Daxx-mediated PPARγ nucleus translocation, leading to the suppression of anti-inflammatory cytokine IL-10 expression. Finally, the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions was abolished by intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα. Our study elucidates the distinct involvement of microglial Pdcd4 in neuroinflammation, suggesting its potential as a therapeutic target for neuroinflammation-related depression.
Insights
Targeting microglial Program cell death protein 4 (Pdcd4) shows antidepressant effects by reducing neuroinflammation. Knocking out Pdcd4 in microglia protected against depressive-like behaviors in mice.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation is implicated in major depressive disorder (MDD) pathogenesis.
- The exact molecular mechanisms linking brain inflammation to MDD require further elucidation.
Purpose of the Study:
- To investigate the role of microglial Program cell death protein 4 (Pdcd4) in lipopolysaccharide (LPS)-induced neuroinflammation and depressive-like behaviors.
- To explore the potential of targeting microglial Pdcd4 as a therapeutic strategy for depression.
Main Methods:
- Generated microglial conditional knockout mice for Pdcd4.
- Administered LPS to mice to induce neuroinflammation and depressive-like behaviors.
- Utilized Western blotting and ELISA to assess protein expression and cytokine levels.
- Administered IL-10 neutralizing antibody (IL-10Rα) via intracerebroventricular injection.
Main Results:
- Microglial Pdcd4 knockout protected against LPS-induced microglial hyperactivation and depressive-like behaviors.
- Microglial Pdcd4 was found to inhibit Daxx-mediated PPARγ nucleus translocation, suppressing anti-inflammatory IL-10 expression.
- The antidepressant effect of microglial Pdcd4 knockout was reversed by IL-10Rα injection.
Conclusions:
- Microglial Pdcd4 promotes LPS-induced neuroinflammatory responses and depressive-like behaviors.
- Targeting microglial Pdcd4 represents a potential therapeutic avenue for neuroinflammation-related depression.
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