Key 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.
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
J Neuroinflammation. 2024 May 31;21(1):143. doi: 10.1186/s12974-024-03142-3.
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.
大脑中促炎和抗炎过程的失调与重度抑郁症（MDD）的发病机制有关，但确切的机制尚不清楚。在这项研究中，我们发现小胶质细胞条件性敲除 Pdcd4 可防止 LPS 诱导的小胶质细胞过度激活和小鼠的抑郁样行为。在机制上，小胶质细胞 Pdcd4 通过抑制 Daxx 介导的 PPARγ 核易位来发挥作用，从而抑制 LPS 触发的神经炎症反应，导致抗炎细胞因子 IL-10 的表达受到抑制。最后，在 LPS 挑战条件下，小胶质细胞 Pdcd4 敲除的抗抑郁作用被脑室注射 IL-10 中和抗体 IL-10Rα 所消除。我们的研究阐明了小胶质细胞 Pdcd4 在神经炎症中的独特作用，表明其可能成为与神经炎症相关的抑郁症的治疗靶点。
