Inducible expression of CXCL1 within the CNS amplifies demyelination in pre-clinical models of multiple sclerosis

Abstract

Abstract The functional role of the ELR+ chemokine CXCL1 in host defense and disease in two pre-clinical mouse models of the human demyelinating disease multiple sclerosis (MS) was assessed. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within GFAP-positive cells were generated and infected intracranially with the neurotropic JHM strain of mouse hepatitis virus (JHMV) or immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 to induce experimental autoimmune encephalomyelitis (EAE). In both JHMV-induced neurologic disease and EAE, overexpression of CXCL1 by astrocytes resulted in increased clinical disease severity. Immunophenotyping cells infiltrating into the central nervous system (CNS) revealed a selective increase in Ly6G+CD11b+ neutrophils (but not Ly6G−Ly6C+CD11b+ monocytes) present within the CNS. In JHMV infected mice and MOG35-55-immunized mice, the T cell response to antigen with regard to proliferation and cytokine production was not altered, nor was trafficking into the CNS affected. In both models, increased CXCL1 expression within the CNS resulted in increased morbidity that correlated with selectively 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 two different mouse models of MS.