Bexarotene alleviates aberrant activation of microglia in early life by regulating the RXRα-PPARγ-NF-κB axis

The early developmental window is a critical period for the structural establishment and functional maturation of the central nervous system. During this stage, the proliferation, morphological remodeling, and phenotypic transformation of microglia are essential for neurogenesis, synaptic pruning, and refinement of neural circuits, and their dysregulation is implicated in multiple neurodevelopmental disorders. However, the molecular mechanisms governing early microglial development remain unclear. Retinoid X receptor α (RXRα), a nuclear receptor with key roles in development and immune regulation, has not been fully characterized in this context. Here, we used a mouse model of early-life stress (maternal separation) to assess its impact on hippocampal microglial development and inflammation, and to delineate the role of RXRα. Early-life stress reduced body weight and increased plasma corticosterone in juvenile mice, decreased microglial branching and induced aberrant activation, and elevated hippocampal IL-1β, IL-6, and NF-κB subunits P50 and P65. Treatment with the RXR agonist bexarotene upregulated hippocampal RXRα, partially restored microglial morphological complexity, and markedly suppressed pro-inflammatory cytokines and NF-κB pathway gene expression. In an in vitro microglial inflammation model, the anti-inflammatory effect of bexarotene was dependent on peroxisome proliferator-activated receptor γ (PPARγ), as inhibition of PPARγ attenuated its actions. These findings identify RXRα as a critical transcriptional regulator maintaining early microglial homeostasis and limiting inflammation and provide a theoretical basis for the application of bexarotene in the treatment of neuroinflammatory damage caused by early-life trauma.