Lipocalin-2 perpetuates postoperative and post-infectious neuroinflammation and anxiety-like behavior

Lipocalin-2 (LCN2) is a pleiotropic cytokine with well-established roles in immune defense, iron metabolism, and inflammation that has been used as a biomarker for kidney injury, cancer, and infection. Recent work has also suggested a role for LCN2 in brain function and behavior, suggesting that LCN2 excess could be a driver of neuropsychiatric complications of infectious and inflammatory conditions. Here, we show that LCN2 levels remain elevated in both the brain and circulation for weeks after an acute infection or simple laparotomy in male and female mice. We used an inducible knockout mouse model to decrease lcn2 expression after recovery from surgery and infection and found that higher brain lcn2 RNA levels predicted persistent neuroinflammation and anxiety-like behavior in survivors. Exogenous LCN2 administration increased in vivo activity of hippocampal CA1 pyramidal cells and increased anxiety-like behavior in male mice. Together, these findings reveal a novel role for LCN2 as a neuroinflammatory mediator of long-term neuropsychiatric dysfunction in infection survivors.