Neuropathological characterization of transgenic mice with astrocyte-directed production of the CXC chemokine ligand 10

Chemokines constitute a large family of chemotactic cytokines which regulate leukocyte trafficking to different target organs during physiological and pathological states. The CXC chemokine ligand (CXCL) 10 (formerly known as IP-10) is induced locally in the central nervous system (CNS) during diverse neuroinflammatory disorders. In the present study, the impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. <br>These glial fibrillary acidic protein (GFAP)-CXCL10 transgenic mice developed spontaneous, transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal and ventricular areas of the brain that were composed of, surprisingly, predominantly neutrophils, and lower numbers of T cells and cells of the monocytic lineage. <br>No phenotypical abnormalities or histological signs of neurodegeneration were evident in the GFAP-CXCL10 mice. In addition, the expression level of a number of inflammation-related genes, including proinflammatory cytokines and chemokines, was not significantly altered in the CNS of the transgenic mice. <br>The recruitment of leukocytes to the CNS of GFAP-CXCL10 mice could be markedly enhanced by peripheral immunization with Complete Freund's Adjuvant (CFA) and pertussis toxin in the absence of CNS-specific autoantigen. This response was accompanied by a transient, moderate increase in the expression level of several proinflammatory chemokine (CCL6 and CCL2), cytokine (TNF-alpha IL-1-alpha and IL-1-betaand other host response genes which are typically upregulated during neuroinflammatory processes (GFAP, EB22/5, ICAM-1 and Mac-1). <br>Flow cytometric expression analysis of the CXCL10 receptor, CXCR3, on <br>brain-infiltrating leukocytes from GFAP-CXCL10 mice indicated that there was significant enrichment for CXCR3-positive cells in the CNS of these mice compared with spleen. The majority of CXCR3-positive cells co-expressed the T cell marker CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. <br>In conclusion, astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced leukocyte recruitment to the CNS, but is not sufficient on its own to promote a degenerative immune pathology. The accumulation of neutrophils in the CNS of GFAP-CXCL10 mice is independent of CXCR3 and hence involves an as yet undefined mechanism.

Author dc:creator

• Boztug, Kaan

Contributors dc:contributor

• Volk, Benedikt

• CXCL10
• IP-10
• CXCR3
• GFAP
• Complete Freund's Adjuvans

Repository record source_url

https://freidok.uni-freiburg.de/data/1791

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:1791