T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis
T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis
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DOI：
10.3390/ijms20030537
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Meissner, Anja
中科院分区：
文献类型：
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作者：
Don-Doncow, Nicholas;Vanherle, Lotte;Meissner, Anja
高血压被认为是认知障碍发生的主要可改变的危险因素。由于血压升高往往伴随着免疫系统的激活，神经炎症的概念在高血压相关的神经变性领域得到了越来越多的关注。特别是，高血压相关的循环T淋巴细胞数量增加和靶器官损伤激发了人们对高血压期间导致炎症相关脑损伤的机制的兴趣。本研究描述了1-磷酸鞘氨醇(S1P)在高血压相关的神经炎症和认知障碍期间对T细胞对大脑的趋化作用的主要贡献。利用Western blotting、流式细胞仪和质谱学方法，我们证明了在血管紧张素II(AngII)诱导的高血压小鼠模型中，高血压刺激神经鞘氨醇激酶1(SphK1)依赖的脑组织S1P浓度的增加。循环血液和脑组织之间明显的S1P梯度的发展与大脑中CD3+T细胞数量的增加有关。用S1P受体调节剂FTY720抑制S1P(1)引导的T细胞趋化，可防止高血压WT小鼠脑CD3表达增加和记忆障碍的发展。总而言之，我们的数据强调了一种新的方法来理解高血压相关的炎症在疾病进展过程中的大脑退变过程。
Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P(1)-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.