Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system
Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system
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DOI：
10.1073/pnas.0903602106
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发表时间：
2009-09-01
影响因子：
11.1
通讯作者：
Linker, Ralf A.
中科院分区：
文献类型：
--
作者：
Stegbauer, Johannes;Lee, De-Hyung;Linker, Ralf A.
血管紧张素II是肾素血管紧张素系统（RAS）的主要效应分子。它对心血管和肾脏系统发挥各种作用，主要通过与血管紧张素II 1型受体（AT 1 R）相互作用，这有助于血压调节和高血压的发展，但也可能介导对免疫系统的影响。在这里，我们研究RAS在髓鞘-少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎（MOG-EAE）中的作用，该模型模拟多发性硬化的许多方面。定量RT-PCR分析显示，在发炎的脊髓和免疫系统，包括抗原呈递细胞（APC）的肾素，血管紧张素转换酶，以及AT 1 R的上调。治疗与肾素抑制剂阿利吉仑，血管紧张素II转化酶抑制剂依那普利，以及预防或治疗应用的AT 1 R拮抗剂氯沙坦，导致MOG-EAE的过程中显着改善。阻断AT 1 R并不直接影响T细胞反应，但显著减少了免疫器官和炎症脊髓中CD 11b（+）或CD 11 c（+）APC的数量。此外，AT 1 R阻断损害了CCL 2、CCL 3和CXCL 10的表达，并减少了CCL 2诱导的APC迁移。我们的研究结果表明RAS在中枢神经系统的自身免疫性炎症中起着关键作用，并将RAS阻断作为多发性硬化症治疗的潜在新靶点。
Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b(+) or CD11c(+) APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.