Department of Anesthesiology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
J Neuroinflammation. 2022 Jul 7;19(1):176. doi: 10.1186/s12974-022-02537-4.
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.
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.
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.
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.
代谢失调和免疫稳态的破坏与包括围手术期缺血性中风在内的围手术期并发症广泛相关。虽然免疫代谢物 S-2-羟戊二酸（S-2HG）是免疫细胞的新兴调节剂，从而引发免疫反应，但尚不清楚 S-2HG 是否以及如何引发围手术期缺血性脑损伤并加重中风后认知功能障碍。
在盲肠切除术 1 天后，通过短暂性大脑中动脉闭塞 60 分钟在 C57BL/6 小鼠中诱导围手术期缺血性中风。使用流式细胞术测量 CD8 T 淋巴细胞的激活和脑血管腔的浸润。进行非靶向代谢组学分析，以检测缺血后分选的 CD8 T 淋巴细胞中的代谢变化。CD8 T 淋巴细胞在体外通过慢病毒转染来动员细胞增殖和分化，然后转移到重组激活基因 1（Rag1）中风小鼠中。
围手术期中风小鼠比单纯中风小鼠表现出更严重的脑缺血损伤和神经功能障碍。CD8 T 淋巴细胞浸润脑实质和神经毒性加重围手术期中风小鼠的脑缺血损伤。CD8 T 淋巴细胞耗竭逆转了围手术期中风小鼠免疫介导的脑缺血脑损伤的加重。围手术期缺血性中风引发外周 CD8 T 细胞中异常的代谢改变，其中 S-2HG 更为丰富。S-2HG 改变 CD8 T 淋巴细胞的体外增殖和分化，并通过增强 CD8 T 淋巴细胞介导的神经毒性来调节免疫介导的缺血性脑损伤和中风后认知功能障碍。
我们的研究表明，S-2HG 信号转导介导的 CD8 T 淋巴细胞的激活和神经毒性可能加重围手术期缺血性脑损伤，并可能成为围手术期缺血性中风的有前途的免疫治疗靶点。
