Lcn2 from neutrophil extracellular traps induces astrogliosis and post-stroke emotional disorders
Yuan Liu, Wei Lin, Zhongfei Bai, Yu‐Wei Ge, Yuanjie Xiao, Feifei Zhu, Jing Zhang, Bingying Wang, Qiyang Li, Li Gao, Yan Li, Chunlei Shan, Jun Nagai, Yiwen Wu, Tian‐Le Xu, Zhengrun Gao
Abstract
Patients with an ischemic stroke are often predisposed to emotional disorders. However, the mechanisms underlying post-stroke emotional disorders (PSEDs) remain unclear. Recent research highlights the role of neuroinflammation, driven primarily by infiltration of circulating immune cells within the brain parenchyma and accompanied by blood-brain barrier (BBB) disruption, in secondary emotional disorders. Combining human cohort and animal model data, we identified serum neutrophil extracellular traps (NETs) as significant contributors to PSEDs. Conditional knockout strategies and -omics analyses convergently identified central NETs as the specific modulator of PSEDs. We further elucidated that astrogliosis is catalyzed by lipocalin 2 (Lcn2) released from NETs, which constituted the core mechanism underlying PSEDs. Additionally, we provided proof-of-concept evidence that transcranial direct current stimulation (tDCS) can suppress Lcn2 release and alleviate PSEDs. Collectively, these findings delineated a distinct peripheral-central neuroimmune interaction pattern following BBB damage and highlighted the potential of non-invasive stimulation in effectively reshaping the neuroimmune environment.