Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling

Abstract

Abstract The imbalance between pro- and anti-inflammation in the brain is related to major depressive disorder (MDD), but the underlying mechanism is largely unknown. Herein, we found that Pdcd4 microglial conditional knockout (Pdcd4 mcKO) protected mice from LPS-induced hyperactivation of microglia and depressive-like behavior. Mechanically, microglial Pdcd4 promoted neuroinflammatory disturbance induced by LPS through inhibiting Daxx mediated PPARγ nucleus translocation and resulted in suppressing the anti-inflammatory cytokine IL-10 expression. Finally, intracerebroventricular injection of the IL-10 neutralizing antibody IL-10Rα abolished the antidepressant effect of microglial Pdcd4 knockout under LPS-challenged conditions. Overall, our research reveals the specific role of microglial Pdcd4 in neuroinflammation, which could be a potential therapeutic target of neuroinflammation-related depression.