Evaluating functional roles of CXCL1:CXCL2 signaling in pre-clinical mouse models of neuroinflammation and disease

ABSTRACT

Intracranial infection with the JHM strain of the mouse hepatitis virus (JHMV), a member of the Betacoronavirus family, causes acute encephalomyelitis resulting in immune-mediated demyelination. JHMV infection is an excellent model to study both viral-induced neurologic disease and the immunologic mechanisms contributing to demyelination and is a well-accepted model for the human demyelinating disease multiple sclerosis (MS). Following JHVM infection of the CNS, the innate immune system is rabidly mobilized and secretion of the ELR+ family of chemokines, including CXCL1, which contribute to multiple cell processes including migration, differentiation, and maturation. Using a transgenic mouse in which the neutrophil chemoattractant CXCL1 can be induced to be overexpressed from astrocytes, we previously showed that sustained neutrophil infiltration exacerbates demyelination and clinical severity in the JHMV model. Subsequently, we wanted to replicate these findings in the prototypic experimental autoimmune encephalomyelitis (EAE) model and also to elucidate the mechanisms by which neutrophils are augmenting white matter damage in the JHMV mouse model of demyelination. In the EAE model we found that sustained infiltration of neutrophils into the CNS increased severity of demyelination and worsened clinical score without affecting the infiltration of other immune cell populations. Additionally, blocking neutrophil over accumulation with anti-CXCR2 antibody ameliorated these negative effects. We also found in the JHMV model that sustained neutrophil infiltration exacerbated demyelination through both direct and indirect effects. Neutrophils in the spinal cord were found to have a more mature phenotype associated with increased granularity and proinflammatory protein production and also polarized other infiltrating immune cells to a more inflammatory phenotype.The CXCR2/CXCL1 signaling pathway is also important for proper myelination of the CNS, specifically in the positional migration and proliferation of oligodendrocyte precursor cells (OPCs) in the developing mouse brain. In addition, CXCR2 signaling has been implicated in regulating remyelination in several pre-clinical models of demyelination. In order to determine the role of CXCR2 signaling on OPCs we developed a mouse model in which Cxcr2 was conditionally ablated following tamoxifen treatment in adult mice. We found using the JHMV model that Cxcr2 silencing on OPCs did not affect clinical disease, infiltrating immune cells, or demyelination. It also had no effect on the structural myelin composition of noninfected transgenic mice. However, we did find that Cxr2 ablation resulted in more mature oligodendroglia and more remyelination at later time points following JHMV infection. (PsycInfo Database Record (c) 2023 APA, all rights reserved)