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

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 alterations in peripheral CD8(+) T cells, in which S-2HG is more abundant. S-2HG alters CD8(+) T lymphocyte proliferation and differentiation ex vivo and modulates the immune-mediated ischemic brain injury and post-stroke cognitive dysfunction by enhancing CD8(+) T lymphocyte-mediated neurotoxicity. CONCLUSION: Our study establishes that S-2HG signaling-mediated activation and neurotoxicity of CD8(+) T lymphocytes might exacerbate perioperative ischemic brain injury and may represent a promising immunotherapy target in perioperative ischemic stroke. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02537-4.