Bioactive dietary polyphenols modulate hippocampal inflammasome activation and sex-specific affective behavioral deficits following peripheral Foxp3

The transcription factor Foxp3 is the lineage-defining marker essential for the development and suppressive function of regulatory T cells (Tregs), which maintain peripheral immune homeostasis. Emerging evidence suggests that this Foxp3+ Treg axis plays a critical role in modulating central neuroimmune signaling and affective behaviors; however, whether a Bioactive Dietary Polyphenol Preparation (BDPP) can effectively modulate or attenuate these neuroinflammatory responses remains unclear. In this study, we assessed how transient Foxp3 depletion influences affective behaviors, microglial responses, and blood-brain barrier integrity within the hippocampus, and whether BDPP treatment could modulate these outcomes. Foxp3 depletion induced sex-dependent behavioral deficits, characterized by depressive-like behavior, impaired motivational drive, and anxiety-related behavior. These behavioral changes coincided with robust hippocampal Caspase-1 activation and microglial remodeling, as quantified by Sholl analysis, indicating an enhanced inflammasome-associated neuroimmune response following peripheral Treg dysfunction. Notably, BBB integrity was preserved across all groups, demonstrating that peripheral immune dysregulation is sufficient to drive central neuroinflammatory and behavioral abnormalities independent of vascular damage. Furthermore, BDPP administration selectively attenuated these behavioral deficits, caspase-1 activation, and the associated microglial changes predominantly in male subjects, whereas females exhibited limited responsiveness. Collectively, these data establish a functional link between peripheral Treg homeostasis and hippocampal immunity, highlighting BDPP as a sex-specific modulator of immune-driven behavioral dysfunction.