Fulminant lymphocytic choriomeningitis virus-induced inflammation of the CNS involves a cytokine-chemokine-cytokine-chemokine cascade

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

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Abstract

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.
Original languageEnglish
JournalJournal of Immunology
Volume182
Issue number2
Pages (from-to)1079-87
ISSN0022-1767
DOIs
Publication statusPublished - 2009
Externally publishedYes

Keywords

  • Animals
  • Antigens, Viral
  • Chemokine CXCL10
  • Chemokines
  • Cytokines
  • Female
  • Glycoproteins
  • Inflammation Mediators
  • Injections, Intraventricular
  • Interferon Type I
  • Lymphocytic Choriomeningitis
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • Mice, Transgenic
  • Peptide Fragments
  • Signal Transduction
  • T-Lymphocyte Subsets
  • Up-Regulation
  • Viral Proteins

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