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  3. Astrocyte-Derived CXCL10 Induces Neuronal Tau Hyperphosphorylation and Cognitive Impairments in Sepsis

Astrocyte-Derived CXCL10 Induces Neuronal Tau Hyperphosphorylation and Cognitive Impairments in Sepsis

  • Neurosci Bull. 2025 Jul 2. doi: 10.1007/s12264-025-01445-w.
Cuiping Guo # 1 2 3,  Hang Ruan # 1,  Wensheng Li 3,  Yi Liu 3,  Abdoul Razak Yacoubou Mahaman 3,  Qian Guo 3,  You Zhou 4,  Rong Liu 3,  Jianzhi Wang 3,  Chenliang Zhou 5,  Xiaochuan Wang 6 7 8 9,  Shusheng Li 10
Affiliations

Affiliations

  • 1 Department of Emergency Medicine and Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Institute of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, 430056, China.
  • 3 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 4 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 5 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China. rm000978@whu.edu.cn.
  • 6 Department of Emergency Medicine and Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wxch@mails.tjmu.edu.cn.
  • 7 Institute of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, 430056, China. wxch@mails.tjmu.edu.cn.
  • 8 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wxch@mails.tjmu.edu.cn.
  • 9 Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. wxch@mails.tjmu.edu.cn.
  • 10 Department of Emergency Medicine and Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. shushengli16@sina.com.
  • # Contributed equally.
PMID: 40601125 DOI: 10.1007/s12264-025-01445-w
Abstract

Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis, yet the underlying mechanisms remain elusive. The current study, using a Lipopolysaccharide (LPS)-induced septic rat model, revealed the hyperphosphorylation of tau and cognitive impairments, accompanied by the release of inflammatory cytokines and activation of glial cells in the hippocampal dentate gyrus region of septic rats. Proteomic and bioinformatic analyses identified C-X-C motif chemokine ligand 10(CXCL10) as a central regulator of neuroinflammation. LPS triggered CXCL10 secretion in astrocytes, and astrocyte-conditioned medium from LPS-treated astrocytes induced tau hyperphosphorylation and synaptic deficits. Recombinant CXCL10 recapitulated these effects in vitro and in vivo. Blocking CXCL10-CXCR3 interaction reversed tau phosphorylation, synaptic impairment, and cognitive decline. Mechanistically, CXCL10-CXCR3 interaction activated CaMKII, driving tau hyperphosphorylation, while CaMKII inhibition restored synaptic protein levels. These findings establish CXCL10 as a key driver of tau pathology in SAE and suggest CXCL10-CXCR3 as a therapeutic target for sepsis-induced cognitive impairments.

Keywords

CXCL10/CXCR3; CaMKII; Cognitive impairment; Sepsis; Tau phosphorylation.

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