The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity

作者：Zhang Faqiang, Mu Niu, Kai-Kai Guo, Yulong Ma, Qiang Fu, Yanhong Liu, Zeguo Feng, Weidong Mi, Long Wang · 发表于：Journal of Neuroinflammation · 年份：2022 · DOI：10.1186/s12974-022-02537-4 · 被引用次数：19 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Intensive Care Unit Cognitive Disorders、Anesthesia and Neurotoxicity Research

Abstract Background Metabolic dysregulation and disruption of immune homeostasis have been widely associated with perioperative complications including perioperative ischemic stroke. Although immunometabolite S-2-hydroxyglutarate (S-2HG) is an emerging regulator of immune cells and thus triggers the immune response, it is unclear whether and how S-2HG elicits perioperative ischemic brain injury and exacerbates post-stroke cognitive dysfunction. Methods Perioperative ischemic stroke was induced by transient middle cerebral artery occlusion for 60 min in C57BL/6 mice 1 day after ileocecal resection. CD8 + T lymphocyte activation and invasion of the cerebrovascular compartment were measured using flow cytometry. Untargeted metabolomic profiling was performed to detect metabolic changes in sorted CD8 + T lymphocytes after ischemia. CD8 + T lymphocytes were transfected with lentivirus ex vivo to mobilize cell proliferation and differentiation before being transferred into recombination activating gene 1 (Rag1 −/− ) stroke mice. Results The perioperative stroke mice exhibit more severe cerebral ischemic injury and neurological dysfunction than the stroke-only mice. CD8 + T lymphocyte invasion of brain parenchyma and neurotoxicity augment cerebral ischemic injury in the perioperative stroke mice. CD8 + T lymphocyte depletion reverses exacerbated immune-mediated cerebral ischemic brain injury in perioperative stroke mice. Perioperative ischemic stroke triggers aberrant metabolic alte...