Neuroimmune Communication at the Blood Brain Barrier

描述（由申请人提供）：神经免疫通讯涉及对感染的生理防御和导致中枢神经系统（CNS）许多疾病的致病事件。这种沟通的关键介质是白细胞介素-1。以下证据表明IL-1作用于血脑屏障细胞以影响CNS：1）功能性IL-1受体（2）中枢注射IL-1后，IL-1反应性即刻早期基因IkappaB α主要在CNS内皮细胞中被诱导表达; 3）在外周和中枢免疫攻击后，在脑内皮细胞中诱导炎性介质，如白藜芦醇;和4）IL-1 r1对于在CNS免疫应答的发展期间介导白细胞穿过BBB的募集是必需的。因此，该提议的中心假设是IL-1通过激活CNS内皮细胞影响CNS。这一假设可以直接在我们最近创建的转基因小鼠中进行测试，我们可以特异性地抑制内皮细胞上IL-1 r1的表达。本申请的长期目标是阐明BBB在介导神经免疫串扰中的作用。使用这些转基因动物，将测试以下特定目的：1）确定IL-1 r1蛋白表达在正常和免疫攻击小鼠的CNS中的分布。2)确定内皮细胞IL-1 r1在介导外周和中枢免疫激发诱导的神经回路激活和功能后果中的作用。3)确定内皮细胞IL-1 r1在血脑屏障白细胞募集中的作用。4)确定内皮细胞IL-1 r1在介导实验性自身免疫性脑脊髓炎（EAE）发生和进展中的作用。该项目的结果应提供一个明确的分析，以确定内皮细胞IL-1 r1在神经免疫相互作用的几个方面的作用。

DESCRIPTION (provided by applicant): Neuroimmune communication has been implicated in both physiological defense against infection and pathogenic events contributing to many disorders of the central nervous system (CNS). A key mediator for this communication is interleukin-1. The following evidences indicate IL-1 acts on cells of the blood brain barrier to affect the CNS: 1) The functional 1L-1 receptor (type I IL-1 receptor, IL-1r1) is mostly expressed on CNS endothelial cells, 2) IL-1-responsive immediate early gene IkappaBalpha is induced primarily in CNS endothelium after central IL-1 injection; 3) inflammatory mediators such as the prostaglandins are induced in brain endothelial cells after both peripheral and central immune challenges; and 4) IL-1r1 is essential for mediating the recruitment of leukocytes across the BBB during the development of CNS immune responses. The central hypothesis of this proposal, therefore, is that IL-1 affects the CNS through the activation of CNS endothelial cells. This hypothesis can be tested directly in our recently created transgenic mice with which we can specifically inhibit the expression of IL-1r1 on endothelial cells. The long range goal of this application is to elucidate the role of BBB in mediating neuroimmune crosstalk. Using these transgenic animals, the following specific aims will be tested: 1) Determine the distribution of IL-1r1 protein expression in the CNS in normal and immunologically challenged mice. 2) Determine the role of endothelial IL-1r1 in mediating the activation of the neural circuits and the functional consequences induced by peripheral and central immune challenges. 3) Determine the role of endothelial IL-1r1 in the recruitment of leukocyte across the BBB. 4) Determine the role of endothelial IL-1r1 in mediating the development and progression of experimental autoimmune encephalomyelitis (EAE). The results of this project should provide a definitive analysis to determine the role of endothelial IL-1r1 in several aspects of neuroimmune interaction.