CNS Pathobiology of IFN-inducible non-ELR CXC Chemokines

描述（由申请人提供）：三种趋化因子CXCL 9、CXCL 10和CXCL 11组成IFN诱导型非ELR CXC趋化因子亚组。这些趋化因子与共同受体CXCR 3和可能的其他受体结合，并参与白细胞运输，但具有其他重叠和不同的功能。在这里，我们假设，由于受体的可用性和使用以及通过其自身的差异基因表达，该趋化因子亚组的成员在炎性神经系统疾病如多发性硬化症和病毒性脑膜脑炎的发病机制中发挥多种多样的作用。是局部诱导的（例如在星形胶质细胞中），并涉及从感染性脑膜脑炎到免疫炎性脱髓鞘病理的各种CNS疾病中的白细胞运输。尽管如此，我们对以下方面知之甚少：（1）CXCL 9、CXCL 10和CXCL 11或CXCR 3在这些和其他CNS炎性疾病病理中的协调空间和时间调节，（2）该亚组中所有三种趋化因子执行的可能CNS功能的谱，以及（3）CXCR 3相对于其他假定受体介导这些趋化因子在CNS中的生物学作用的相对作用。因此，在本提议的第一个具体目标中，我们将定义CXCL 9、10和11以及CXCR 3在不同的神经炎性病理中的协调调节以及时间和空间表达，包括：（i）LPS诱导的内毒素血症，（ii）病毒感染（即淋巴细胞性脉络丛脑膜炎和MHV脑脊髓炎），和（iii）髓鞘少突胶质细胞肽（MOG）免疫诱导的实验性自身免疫性脑脊髓炎（EAE）。此外，将在缺乏IFN-γ基因的小鼠中研究这些疾病范例，以确定这种关键细胞因子的调节作用。在第二个具体目标中，我们将评估CXCL 9、CXCL 10和CXCL 11在活体CNS中的体内功能后果和作用机制。转基因小鼠将产生每种靶向星形胶质细胞的趋化因子。这些所谓的GF-CXCL转基因小鼠将被评估为自发的以及疾病诱导的CNS改变。此外，我们将阐明这些趋化因子在中枢神经系统中的血管抑制功能。为此，我们将GF-CXCL小鼠与脑内有慢性血管生成的GF-IL-6转基因小鼠杂交。在最后的具体目标中，我们将利用最近开发的缺乏CXCR 3受体的突变小鼠来确定这种或其他假定受体在介导CXCL 10的生物学作用中的作用。将检查CXCR 3缺陷小鼠在CNS病毒感染或MOG-EAE诱导后以及与GF-CXCL 10转基因小鼠杂交后的神经病理学结果。我们的研究结果将填补我们目前知识的巨大空白，并提供关于IFN-γ诱导的非ELR CXC趋化因子的CNS病理生物学的重要新信息。

DESCRIPTION (provided by applicant): Three chemokines, CXCL9, CXCL10 and CXCL11, comprise the IFN-inducible non-ELR CXC chemokine subgroup. These chemokines bind to a common receptor CXCR3 and possibly additional receptors and are involved in leukocyte trafficking but have other overlapping as well as distinct functions. Here we hypothesize that as dictated by receptor availability and usage as well as through their own differential gene expression, members of this chemokine subgroup play multiple and diverse roles in the pathogenesis of inflammatory neurological diseases such as multiple sclerosis and viral meningoencephalitis.CXCL10 which is widely studied by us, as well as others, is induced locally (e.g. in astrocytes) and implicated in leukocyte trafficking in a variety of CNS diseases ranging from infectious meningoencephalitides to immunoinflammatory demyelinating pathologies. Despite this, we know very little about: (1) the coordinate spatial and temporal regulation of CXCL9, CXCL10 andCXCL11 or CXCR3 in these and other CNS inflammatory disease pathologies, (2) the spectrum of possible CNS functions performed by all three chemokines in this subgroup, and (3) the relative role of CXCR3 versus other putative receptors inmediating the biological actions of these chemokines in the CNS. Accordingly, in the first specific aim of this proposal we will define the coordinate regulation and temporal and spatial expression of CXCL9, 10 &l 1 and CXCR3 in distinct neuroinflammatory pathologies including: (i) LPS-induced endotoxemia, (ii) virus infection (i.e. lymphocytic choriomeningitis and MHV encephalomyelitis), and (iii) myelin oligodendrocyte peptide (MOG) immunization-induced experimentalautoimmune encephalomyelitis (EAE). Further, these disease paradigms will be studied in mice lacking the IFN-gamma gene in order to establish the regulatory role of this key cytokine. In the second specific aim, we will assess the in vivo functional consequences and mechanisms of action of CXCL9, CXCL10 and CXCL11 in the living CNS. Transgenic mice will be generated with the production of each these chemokines targeted to the astrocyte. These so-called GF-CXCL transgenicmice will be assessed for spontaneous as well as disease-induced alterations in the CNS. In addition, we will elucidate the angiostatic functions of these chemokines in the CNS. For this purpose we will interbreed GF-CXCL mice with GF-IL-6transgenic mice that have chronic angiogenesis in the brain. In the final specific aim we will make use of recently developed mutant mice that lack the CXCR3 receptor to determine the role of this or other putative receptors in mediating the biological actions of CXCL10. CXCR3 deficient mice will be examined for neuropathologic outcomes following CNS viral infection or induction of MOG-EAE as well as in intercrosses with the GF-CXCL10 transgenic mice. The results from our studies will fill in large gaps in our current knowledge and provide important new information as to the CNS pathobiology of the IFN-gamma-inducible non-ELR CXC chemokines.