Leukocyte Infiltration, But Not Neurodegeneration, in the CNS of Transgenic Mice with Astrocyte Production of the CXC Chemokine Ligand 10

Abstract

The CXC chemokine ligand (CXCL)10 is induced locally in the CNS in diverse pathologic states. The impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. These glial fibrillary acidic protein (GF)-CXCL10 transgenic mice spontaneously developed transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal, and ventricular regions of the brain that were composed of, surprisingly, mainly neutrophils and, to a lesser extent, T cells. No other overt pathologic or physical changes were evident. In addition, the cerebral expression of a number of inflammation-related genes (e.g., cytokines) was not significantly altered in the transgenic mice. The extent of leukocyte recruitment to the brain could be enhanced markedly by peripheral immunization of GF-CXCL10 mice with CFA and pertussis toxin. This was paralleled by a modest, transient increase in the expression of some cytokine and chemokine genes. Analysis of the expression of the CXCL10 receptor, CXCR3, by the brain-infiltrating leukocytes from immunized GF-CXCL10 transgenic mice revealed a significant enrichment for CXCR3-positive cells in the CNS compared with spleen. The majority of cells positive for CXCR3 coexpressed CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. Thus, while astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced recruitment of leukocytes to the CNS, this is not associated with activation of a degenerative immune pathology. Finally, the accumulation of neutrophils in the brain of GF-CXCL10 transgenic mice is apparently independent of CXCR3 and involves an unknown mechanism.

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

“…The lack of histopathology induced by IFN-␥-induced expression of chemokines in the CNS in the present study stands in contrast to results obtained by transgenic overexpression. Mice expressing CXCL10 in astrocytes showed spontaneous leukocyte accumulation in perivascular, meningeal, and ventricular areas, but did not show astrocyte activation or other evidence of brain pathology (46). Similarly, myelin basic protein promoter-driven transgenic expression of CCL2 in the CNS led to perivascular accumulation of monocytes/macrophages that did not penetrate into the brain parenchyma and was not associated with brain pathology (47).…”

“…The leukocyte extravasation reported in these transgenic mice may reflect differences in the cellular source and location of chemokine production, as well as the cumulative effects of lifetime expression, as contrasted with the present study in which the increase in chemokine expression resulted from de novo administration of IFN-␥ in adulthood. However, in both of the transgenic models mentioned, as well as another transgenic model with CCL2 expression in astrocytes, leukocyte recruitment to the CNS was substantially increased following peripheral administration of infection-related stimuli (LPS) (47) or Ptx and CFA (46,48).…”

The Type I Interferon-α Mediates a More Severe Neurological Disease in the Absence of the Canonical Signaling Molecule Interferon Regulatory Factor 9

“…RNase protection assays (RPAs) were performed and analyzed as described previously (Asensio and Campbell, 1997). Multiprobe sets used for RPA included IFN-regulated genes (Asensio et al, 2001), STAT and SOCS (Maier et al, 2002), cytokines (Hobbs et al, 1993), interferons (Asensio et al, 1999), and chemokines (Asensio and Campbell, 1997;Boztug et al, 2002).…”

The functional avidity of virus‐specific CD8+ T cells is down‐modulated in Borna disease virus‐induced immunopathology of the central nervous system

“…Down-regulation of antiviral CD8 + T cell responses in persistent virus infections has been shown to involve epitope escape [36], deletion of antigen-specific cells [29,37], and down-regulation of effector functions [29,37,38]. In persistently BDV-infected mice, we found sustained presence of CD8 + T cells in the CNS specific for the immunodominant epitope.…”