STING Driving Synaptic Phagocytosis of Hippocampal Microglia/Macrophages Contributes to Cognitive Impairment in Sepsis-Associated Encephalopathy in Mice

  • CNS Neurosci Ther. 2024 Dec;30(12):e70166. doi: 10.1111/cns.70166.
Xin Lv  1  2 ,  Min Jia  1 ,  Xiao Feng  1 ,  Jia-Xiong Jian  2 ,  Jian-Jun Yang  1 ,  Da-Qing Ma  3  4 ,  Mu-Huo Ji  5 ,  Yu-Gang Diao  6 ,  Jin-Chun Shen  2
Affiliations
  • 1. Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2. Department of Anesthesiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3. Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
  • 4. Perioperative and Systems Medicine Laboratory, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  • 5. Department of Anesthesiology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 6. Department of Anesthesiology, General Hospital of Northern Theater Command, Shenyang, China.
PMID: 39699038 DOI: 10.1111/cns.70166
Abstract

Background: Sepsis-associated encephalopathy (SAE) is a serious neurologic complication in septic patients with poor prognoses. There is increasing evidence that stimulator of interferon genes (STING) plays a crucial role in neuroinflammation and cognitive impairment. However, whether sepsis associated with STING changes contributes to cognitive impairment is unknown.

Methods: Male adult mice received lipopolysaccharide (LPS) injection (a single dose of 4 mg/kg; i.p. injection) and 30 min later, they were injected with STING inhibitor C-176 (a single dose of 30 mg/kg, i.p. injection). Behavioral assessments, biochemical measurements, in vivo and ex vivo electrophysiology techniques were conducted to investigate the association between LPS-induced STING overexpression and cognitive function.

Results: Cognitive impairment was associated with STING overexpression and activation of microglia/macrophages. Phagocytosis of microglia/macrophages as well as complement C1q release were increased after LPS injection, leading to abnormal pruning synapses, synaptic transmission reduction, long-term potentiation (LTP) impairment, as well as abnormal theta oscillation in the hippocampus. Notably, STING inhibitor C-176 significantly reversed these changes.

Conclusions: Sepsis-induced STING overexpression in microglia/macrophages may lead to synaptic loss, abnormal theta oscillation and LTP impairment through microglia/macrophages activation and complement C1q modulation, ultimately resulting in cognitive impairment.

Keywords
C1q; microglia/macrophages; sepsis‐associated encephalopathy; stimulator of interferon genes; synaptic plasticity.
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