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许多中枢神经系统(CNS)紊乱的致病事件。这种交流的一个关键媒介是白介素1。以下证据表明，IL-1作用于血脑屏障细胞影响中枢神经系统：1)功能性的1L-1受体(I型IL-1受体，IL-1r1)主要表达于中枢神经系统内皮细胞，2)IL-1应答的即刻早期基因IkappaBalpha主要在中枢神经系统内皮细胞诱导，3)周围和中枢免疫攻击后，脑内皮细胞均诱导前列腺素等炎症介质的产生，4)IL-1r1在中枢神经系统免疫应答过程中介导白细胞跨血脑屏障的募集。因此，这一建议的中心假设是，IL-1通过激活中枢神经系统内皮细胞来影响中枢神经系统。这一假设可以直接在我们最近创造的转基因小鼠身上得到验证，我们可以用它特异性地抑制内皮细胞上IL-1r1的表达。这项应用的长期目标是阐明血脑屏障在调节神经免疫串扰中的作用。利用这些转基因动物，将测试以下特定目的：1)确定IL-1r1蛋白在正常和免疫攻击小鼠中枢神经系统的表达分布。2)确定内皮细胞IL-1r1在介导神经回路激活中的作用以及外周和中枢免疫刺激所引起的功能后果。3)确定内皮细胞IL-1r1在白细胞跨血脑屏障募集中的作用。4)探讨内皮细胞IL-1r1在实验性自身免疫性脑脊髓炎(EAE)发生发展中的作用。该项目的结果应该为确定内皮细胞IL-1r1在神经免疫相互作用的几个方面的作用提供明确的分析。

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.