Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination

Abstract

The functional role of the ELR+ chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within GFAP-positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain and spinal cord that correlated with increased frequency of Ly6G+CD11b+ neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells and there was no difference in control of JHMV replication compared to control mice indicating T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1-transgenic mice reduced the severity of demyelination in mice arguing a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and neutrophils can contribute to this process in a model of viral-induced neurologic disease.

Neutrophils and viral-induced neurologic disease

“…Dox-induced overexpression of CXCL1 did not enhance control of viral replication within the CNS as both infected double and single tg mice exhibited similar viral titers at defined times post-infection (p.i.) nor were there differences in either frequency or numbers of virus-specific CD4+ and CD8+ T cells within the CNS of double tg mice compared to single tg mice [26]. However, Doxtreatment of JHMV-infected double tg mice resulted in increased clinical disease and mortality when compared to infected single tg mice [26].…”

“…infection of Doxtreated double tg mice with JHMV resulted in a selective increased expression of CXCL1 mRNA transcripts and protein within the brain and spinal cords when compared to Dox-treated single tg mice infected with JHMV (Fig. 1C) [26]. Dox-induced overexpression of CXCL1 did not enhance control of viral replication within the CNS as both infected double and single tg mice exhibited similar viral titers at defined times post-infection (p.i.)…”

“…In attempt to better understand how neutrophils influence both host defense and disease following CNS viral infection, we have recently engineered transgenic mice to utilize the tetracycline-controlled transcriptional activation system in which the human glial fibrillary acidic protein (hGFAP) promoter drives expression of a modified version of the reverse tetracycline transactivator protein (rtTA*M2) [26] ( Fig. 1A).…”

“…Double transgenic (tg) mice (pBI-CXCL1-rtTA) and single tg mice (pBI-CXCL1) were generated; characterization of double tg mice revealed Dox-dependent expression of CXCL1 from cultured astrocytes as determined by ELISA (Fig. 1B) [26]. I.c.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…study of freshly sorted mouse NG2 glia [131] Neuronal survival [191] C-X-C Motif Chemokine Ligand 10, CxCl1 Gene expr. study of cultured mouse NG2 glia exposed to Il17 or Tnf [158,192] Neuroinflammation [193] C-X-C Motif Chemokine Ligand 10, CxCl10 CM of cultured mouse NG2 glia [97] Neuroinflammation [194] C-X3-C Motif Chemokine Ligand 1, Cx3Cl1 CM of cultured mouse NG2 glia [97] Regulation of synapses activity and plasticity, brain functional connectivity and adult hippocampal neurogenesis [195] C-C Motif Chemokine Ligand 7, Ccl7 Gene expr. study of cultured mouse NG2 glia exposed to Il17 [192] Neuroinflammation [196][197][198] Granulocyte-Macrophage Colony Stimulating Factor, GM-CSF or Csf2…”