Preclinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological modulation of inflammatory cytokines in ischemic stroke. Experimental evidence shows that targeting tumor necrosis factor (TNF) and interleukin (IL)-1 holds promise, and these cytokines are considered prime targets in the development of new stroke therapies. So far, however, information on the cellular expression of TNF and IL-1 in the human ischemic brain is sparse. We studied 14 cases of human post-mortem ischemic stroke, representing 21 specimens of infarcts aged 1 to > 8 days. We characterized glial and leukocyte reactions in the infarct/peri-infarct (I/PI) and normal-appearing tissue (NAT) and the cellular location of TNF, TNF receptor (TNFR)1 and TNFR2, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1Ra). The immunohistochemically stained tissue sections received a score reflecting the number of immunoreactive cells and the intensity of the immunoreactivity (IR) in individual cells where 0 = no immunoreactive cells, 1 = many intermediately to strongly immunoreactive cells, and 2 = numerous and intensively immunoreactive cells. Additionally, we measured blood TNF, TNFR, and IL-1 levels in surviving ischemic stroke patients within the first 8 h and again at 72 h after symptom onset and compared levels to healthy controls. We observed IL-1α and IL-1β IR in neurons, glia, and macrophages in all specimens. IL-1Ra IR was found in glia, in addition to macrophages. TNF IR was initially found in neurons located in I/PI and NAT but increased in glia in older infarcts. TNF IR increased in macrophages in all specimens. TNFR1 IR was found in neurons and glia and macrophages, while TNFR2 was expressed only by glia in I/PI and NAT, and by macrophages in I/PI. Our results suggest that TNF and IL-1 are expressed by subsets of cells and that TNFR2 is expressed in areas with increased astrocytic reactivity. In ischemic stroke patients, we demonstrate that plasma TNFR1 and TNFR2 levels increased in the acute phase after symptom onset compared to healthy controls, whereas TNF, IL-1α, IL-1β, and IL-1Ra did not change. Our findings of increased brain cytokines and plasma TNFR1 and TNFR2 support the hypothesis that targeting post-stroke inflammation could be a promising add-on therapy in ischemic stroke patients.

中文翻译：

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缺血性中风后人脑和血液中 TNF 和 IL-1 系统的表征。


临床前和临床概念验证研究表明炎症细胞因子的药理学调节在缺血性中风中的有效性。实验证据表明，针对肿瘤坏死因子 (TNF) 和白细胞介素 (IL)-1 的治疗有希望，并且这些细胞因子被认为是开发新中风疗法的主要靶点。然而，迄今为止，有关人缺血脑中 TNF 和 IL-1 细胞表达的信息还很少。我们研究了 14 例人类死后缺血性中风病例，代表 21 个 1 至 > 8 天的梗死样本。我们表征了梗塞/梗塞周围 (I/PI) 和正常组织 (NAT) 中的胶质细胞和白细胞反应，以及 TNF、TNF 受体 (TNFR)1 和 TNFR2、IL-1α、IL-1β、和IL-1受体拮抗剂（IL-1Ra）。免疫组织化学染色的组织切片获得的分数反映了单个细胞中免疫反应性细胞的数量和免疫反应性 (IR) 的强度，其中 0 = 无免疫反应性细胞，1 = 许多中度至强免疫反应性细胞，2 = 大量且强烈的免疫反应性细胞。此外，我们还测量了存活的缺血性中风患者在症状出现后的前 8 小时内和 72 小时内的血液 TNF、TNFR 和 IL-1 水平，并将其水平与健康对照进行比较。我们在所有标本的神经元、神经胶质细胞和巨噬细胞中观察到 IL-1α 和 IL-1β IR。除了巨噬细胞外，IL-1Ra IR 还存在于神经胶质细胞中。 TNF IR 最初发现于位于 I/PI 和 NAT 的神经元中，但在较老的梗塞灶中的神经胶质细胞中增加。所有样本中巨噬细胞中的 TNF IR 均增加。 TNFR1 IR 在神经元、神经胶质细胞和巨噬细胞中发现，而 TNFR2 在 I/PI 和 NAT 中仅由神经胶质细胞表达，在 I/PI 中由巨噬细胞表达。 我们的结果表明，TNF 和 IL-1 由细胞亚群表达，TNFR2 在星形胶质细胞反应性增加的区域表达。在缺血性中风患者中，我们证明与健康对照相比，症状出现后的急性期血浆 TNFR1 和 TNFR2 水平升高，而 TNF、IL-1α、IL-1β 和 IL-1Ra 没有变化。我们对脑细胞因子和血浆 TNFR1 和 TNFR2 增加的发现支持这样的假设：针对中风后炎症可能是缺血性中风患者的一种有前景的附加疗法。