2. Academic Validation
  3. Lcn2 from neutrophil extracellular traps induces astrogliosis and post-stroke emotional disorders

Lcn2 from neutrophil extracellular traps induces astrogliosis and post-stroke emotional disorders

  • Neuron. 2025 Oct 10:S0896-6273(25)00706-8. doi: 10.1016/j.neuron.2025.09.018.
Yuan Liu 1,  Wei Lin 2,  Zhongfei Bai 3,  Yuting Ge 1,  Yuanjie Xiao 1,  Feifei Zhu 3,  Jing Zhang 3,  Bingying Wang 1,  Qiyang Li 1,  Li Gao 4,  Yan Li 1,  Chunlei Shan 5,  Jun Nagai 6,  Yiwen Wu 7,  Tian-Le Xu 8,  Zhengrun Gao 9
Affiliations

Affiliations

  • 1 Department of Neurology, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, P.R. China.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215021, P.R. China.
  • 3 Department of Neurology and Neurological Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital, Shanghai Sunshine Rehabilitation Center, School of Medicine, Tongji University, Songjiang, Shanghai 201619, P.R. China.
  • 4 Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, Shanxi, P.R. China.
  • 5 Yuanshen Rehabilitation Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
  • 6 Laboratory for Glia-Neuron Circuit Dynamics, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 7 Department of Neurology & Institute of Neurology, Ruijin Hospital, affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200025, P.R. China. Electronic address: wyw11380@rjh.com.cn.
  • 8 Department of Anesthesiology, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, P.R. China; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China. Electronic address: xu-happiness@shsmu.edu.cn.
  • 9 Department of Neurology, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 201600, P.R. China. Electronic address: zrgao@shsmu.edu.cn.
PMID: 41075784 DOI: 10.1016/j.neuron.2025.09.018
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.

Keywords

Lcn2; NETs; neuroimmune environment; post-stroke emotional disorders; tDCS.

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