Pivotal role of cerebral interleukin-17-producing γδT cells in the delayed phase of ischemic brain injury
Pivotal role of cerebral interleukin-17-producing γδT cells in the delayed phase of ischemic brain injury
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DOI：
10.1038/nm.1999
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发表时间：
2009-08-01
期刊：
影响因子：
82.9
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Shichita, Takashi;Sugiyama, Yuki;Yoshimura, Akihiko
淋巴细胞的募集和活化与脑缺血再灌注损伤的进展有关，但特定淋巴细胞亚群和细胞因子在卒中中的作用仍有待阐明。在这里，我们证明了T细胞浸润到大脑中，以及细胞因子白细胞介素-23（IL-23）和IL-17，在脑梗死和伴随的神经功能缺损的演变中具有关键作用。通过免疫抑制剂FTY 720阻断T细胞浸润到脑中减少I/R诱导的脑损伤。IL-23主要来源于浸润的巨噬细胞，其表达在I/R后第1天增加，而IL-17水平在第3天后升高，并且这种IL-17的诱导依赖于IL-23。这些数据，连同对IL-17和IL-23基因破坏的小鼠的分析，表明IL-23在I/R脑损伤的即时阶段起作用，而IL-17在I/R损伤的延迟阶段中具有重要作用，在该延迟阶段中，凋亡性神经元死亡发生在半影区。细胞内细胞因子染色显示，γ δ T淋巴细胞，而不是CD 4（+）辅助T细胞，是IL-17的主要来源。此外，γ δ T淋巴细胞的耗竭改善了I/R损伤。我们认为，T淋巴细胞，包括γ δ T淋巴细胞，可能是一个治疗靶点，用于减轻炎症事件，放大脑缺血的初始损伤。
Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gamma delta T lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gamma delta T lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gamma delta T lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.