Lactoferrin alleviates LPS-induced neuroinflammation and depressive-like behavior in mice by regulating microglial...

Excessive neuroinflammation and imbalance in microglial M1/M2 polarization play crucial roles in the pathogenesis of depression. Lactoferrin (Lf) has been demonstrated to alleviate depression-like symptoms, yet the underlying mechanisms of its antidepressant effects remain incompletely understood. Herein, we demonstrate that Lf alleviates lipopolysaccharide (LPS)-induced depression-like behaviors and synaptic damage in mice. Moreover, Lf attenuated the activation of astrocytes and microglia in the hippocampal region of mice, promoted the shift of microglial phenotype from M1-like to M2-like, and suppressed the release of inflammatory factors. Mechanistically, we demonstrated that Lf regulates glycolytic levels through suppression of the HIF-1α/NF-κB pathway, thereby promoting the transition from M1 to M2 polarization in LPS-induced BV2 cells and subsequently modifying the neuronal microenvironment in vitro. Therefore, exogenous supplementation of Lf might suppress LPS-induced neuroinflammation by reprogramming microglial metabolism, highlighting its preclinical potential in inflammation-associated depressive phenotypes.