The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity.
J Neuroinflammation
; 19(1): 176, 2022 Jul 07.
Article
in En
| MEDLINE
| ID: mdl-35799259
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 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Injuries
/
Brain Ischemia
/
Stroke
/
Cognitive Dysfunction
/
Ischemic Stroke
Limits:
Animals
Language:
En
Journal:
J Neuroinflammation
Journal subject:
NEUROLOGIA
Year:
2022
Document type:
Article
Affiliation country:
China