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

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.

Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity

“…For example, in gliomas and hematologic malignancies, the proliferation and activation of T cells, NK cells, macrophages, and DCs, as well as the complement system, are constrained under a high D-2-HG burden [ 114 ]. Conversely, L-2-HG differs from D-2-HG in promoting T cell proliferation and differentiation [ 122 ]. However, since the role of humoral immunity in the anti-tumor immune response remains unclear, detailed reports on the regulation of B cells by 2-HG are currently lacking.…”

“…At first, overexpression of L2HGDH in CD8 + T cells was used to investigate the decrease of L-2-HG in immune-mediated ischemic brain injury. L-2-HG was found to significantly accumulate after ischemic stress and exacerbated cognitive dysfunction in Rag 1 −/− mice by promoting the proliferation and differentiation of CD8 + T lymphocytes into effector T lymphocytes [ 122 ]. In tumor tissues, HIF-1α is a major stimulus to synthesize multiple metabolites in CD8 + T cells, among which L-2-HG ranks at the top level.…”

“…The results indicated a notable upregulation of NKG2D ligand expression in response to DAC treatment, concomitant with a marked inhibition of tumor proliferation. Notably, this inhibition was observed to be dependent on the presence of NK cells, as the effect was abolished when NK cells were depleted [ 122 ].…”

Tryptophan-rich diet and its effects on brain Tregs in alleviating neuroinflammation and cognitive impairment

“…Tregs secrete inhibitory in ammatory factors such as IL-10 and TGF-β, which suppress the activation of effector cells, including T and B lymphocytes, macrophages, and dendritic cells, and inhibit their in ltration into effector brain regions. Tregs that in ltrate the brain can also exert immunosuppressive effects, possibly by modulating the survival conditions of cytotoxic T cells, leading to their apoptosis [11]. In their study, Tian et al discovered signi cant in ltration of Tregs in the hippocampal region, with upregulation of IL-10 mRNA expression, indicating their role in suppressing immune responses [12].…”

Multifunctional IrOx Neural Probe for In Situ Dynamic Brain Hypoxia Evaluation

“…Injury to the central and peripheral nervous systems is often permanent, which can be devastating for patients and their families. Perioperative cerebral ischemia and hypoxia are one of the main inducements that lead to temporary or permanent brain dysfunction; especially, cardiac surgery and carotid endarterectomy are associated with the highest risk for perioperative cerebral ischemia and hypoxia, with an incidence of 4–5% . On the other hand, neonatal hypoxic-ischemic encephalopathy (NHIE) resulting from perinatal asphyxia in term or near-term newborns is the prevalent cause of morbidity and mortality in children worldwide .…”