Astrocyte-Derived CXCL10 Induces Neuronal Tau Hyperphosphorylation and Cognitive Impairments in Sepsis
Cuiping Guo1,2,3 · Hang Ruan1 · Wensheng Li3 · Yi Liu3 · Abdoul Razak Yacoubou Mahaman3 · Qian Guo3 · You Zhou4 · Rong Liu3 · Jianzhi Wang3 · Chenliang Zhou4 · Xiaochuan Wang1,2,3,5 · Shusheng Li11 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 Afective 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 Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
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
Sepsis; CXCL10/CXCR3; Tau phosphorylation; CaMKII; Cognitive impairment
