UC Irvine

Chemokines and their cognant receptors have been identified as an essential immune component in attracting activated immune cells into the central nervous system (CNS) following experimental infection with the neurotropic JHM strain of mouse hepatitis (JHMV) as well as within the experimental autoimmune encephalomyelitis (EAE) model of Multiple Sclerosis (MS). The primary focus of this dissertation is to investigate how ELR-chemokine signaling within the CNS regulates neuroinflammation and neurologic disease.

To this end, we have generated a doxycycline (Dox) inducible CXCL1 overexpressing mouse line to assess how overproduction of this chemokine from astrocytes impacts host-defense responses and the demyelinated disease that results following JHMV infection. Overexpression of CXCL1 enhanced the accumulation of CXCR2-expressing neutrophils in the CNS without impacting BBB permeability or the infiltration of inflammatory leukocytes. Neutrophils were found to accumulate within the parenchyma during the persistent phase of disease and this was associated with severe white matter demyelination. These data suggest that chronic CXCL1 expression from the CNS can amplify JHMV-induced neurologic disease that is neutrophil dependent.

We next investigated if loss of CXCR2 signaling in oligodendroglia lineage cells results in altered immunopathogenesis within the JHMV and EAE models of demyelination. Using a tamoxifen-inducible Cre-ERT2 transgenic mouse system, we induced ablation of Cxcr2 in oligodendrocytes and subsequently infected mice with JHMV or immunized with a peptide derived from myelin oligodendrocyte glycoprotein (MOG) to induce EAE disease. Interestingly, EAE-induced Cxcr2 fl/fl mice treated with tamoxifen displayed dampened disease severity and this was associated with reduced expression of inflammatory cytokines and chemokines in the CNS, as well as a significant reduction in the infiltration of neutrophils, macrophages and IFN-γ-secreting CD4+ T cells. These data implicates CXCR2-signaling in oligodendrocytes as an amplifier of neuroinflammation and demyelination within the context of the autoimmune EAE model of demyelination. Conversely, tamoxifen-treated Cxcr2 fl/fl mice infected with JHMV resulted in a similar host-defense response as well as disease progression compared to control animals, suggesting that CXCR2 signaling in oligodendrocytes within the context of JHMV infection of the CNS does not have a prominent role in promoting chronic JHMV-induced demyelinating disease.