Down-regulation of lipocalin-2 alleviates depressive-like behaviors in mice through modulation of microglial activation.

Although the pathophysiological underpinnings of major depressive disorder (MDD) are increasingly recognized to involve microglia-mediated neuroinflammation, the underlying molecular processes are still not fully understood. To identify key molecular regulators associated with neuroinflammatory processes, we conducted transcriptomic analysis on hippocampus tissue from chronic unpredictable stress (CUS) mouse models, as well as in vitro microglial inflammation models. Here, we identified lipocalin-2 (LCN2) as a crucial mediator of these neuroinflammatory processes. The expression of LCN2 was significantly upregulated in both MDD patients and CUS mice, and its expression level was positively correlated with the severity of depressive symptoms. In vitro experiments demonstrated that LCN2 knockdown effectively suppresses pro-inflammatory activation of primary microglia. Furthermore, in vivo studies revealed that inhibition of LCN2 expression via gene silencing or neutralizing antibodies markedly alleviates depressive-like behaviors in CUS mice. Mechanistic investigations indicated that knockdown of LCN2 inhibits mitochondrial dynamics imbalance of microglia and then inhibits its proinflammatory activation, thereby reducing neuroinflammation. This study not only identifies a promising therapeutic target for anti-neuroinflammatory interventions in depression but also provides systematic evidence that LCN2-induced mitochondrial dysfunction plays a pivotal role in the pathogenesis and progression of MDD.