CNS Pathobiology of IFN-inducible non-ELR CXC Chemokines

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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.