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Fulminant Lymphocytic Choriomeningitis Virus-Induced Inflammation of the CNS Involves a Cytokine-Chemokine-Cytokine-Chemokine Cascade¹

Jeanette E. Christensen^*, Stine Simonsen^*, Christina Fenger, Maria R. Sørensen^*, Torben Moos, Jan P. Christensen^*, Bente Finsen and Allan R. Thomsen^2,*

^* University of Copenhagen, Department of International Health, Immunology and Microbiology, Copenhagen, Denmark; University of Southern Denmark, Medical Biotechnology Center, Institute of Medical Biology, Odense, Denmark; and Aalborg University, Department of Health Science and Technology, Aalborg, Denmark

Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8⁺ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8⁺ T cell accumulation in the neural parenchyma is impaired, and only 30–50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular source of CXCL10. We found that expression of CXCL10 initially depends on signaling through the type I IFN receptor, while late expression and up-regulation requires type II IFN produced by the recruited CD8⁺ T cells. Throughout the infection, the producers of CXCL10 are exclusively resident cells of the CNS, and astrocytes are the dominant expressors in the neural parenchyma, not microglial cells or recruited bone marrow-derived cell types. These results are consistent with a model suggesting a bidirectional interplay between resident cells of the CNS and the recruited virus-specific T cells with astrocytes as active participants in the local antiviral host response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Danish Medical Research Council, the Lundbeck Foundation, and the Novo Nordisk Foundation. J.E.C. is the recipient of a post doctoral fellowship from the Danish Medical Research Council.

² Address correspondence and reprint requests to Dr. Allan Randrup Thomsen, Department of International Health, Immunology and Microbiology, The Panum Institute, Building 22.5, 3C Blegdamsvej, Copenhagen N, Denmark. E-mail address: athomsen{at}sund.ku.dk

³ Abbreviations used in this paper: MS, multiple sclerosis; LCMV, lymphocytic choriomeningitis virus; i.c., intracerebral; 2'-5' OAS, 2'-5'-oligoadenylate synthetase 1A; p.i., post infection; WT, wild type; Q-PCR, quantitative PCR; AP, alkaline phosphatase; GFAP, glial fibrillary acidic protein; DAPI, 4',6-diamidino-2-phenylindole; CC, corpus callosum; EAE, experimental autoimmune encephalomyelitis.