Immune mediators of central nervous system demyelination and remyelination Public Deposited

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  • March 21, 2019
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  • Chen, Vivian Susan
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The principal goal of an immune response is to protect the host from pathogens, maintain tissue homeostasis and/or to repair damaged tissue. However, an inappropriate or prolonged immune response may be detrimental. Neuroinflammation is an integral component of demyelinating disease, such as multiple sclerosis, and often leads to oligodendrocyte damage and depletion. Here, we report on two immune mediators, interleukin-1 (IL-1) and lymphocyte activation gene-3 (LAG-3, CD223), and their role in demyelination and recovery. IL-1 can be clinically beneficial or detrimental in human diseases. In this study, we examined the individual roles of IL-1α and IL-1β and their effects on myelination and cellular populations during neurodegeneration and recovery. After extensive backcrossing of IL-1α-/-, IL-1β-/-, and IL-1α-/-β-/- mice onto the C57BL/6 background, we demonstrate that IL- 1α and IL-1β do not exacerbate cuprizone-induced demyelination and do not contribute to subsequent remyelination. However, an interesting phenotype emerged in which IL-1β-/- and IL-1α-/-β-/- mice show reduced numbers of mature oligodendrocytes in the corpus callosum, before and after cuprizone treatment. LAG-3 is a membrane-bound glycoprotein that is involved in negative regulation of T cell activity and clonal expansion through its interaction with major histocompatibility complex class II (MHCII). Our study is the first to demonstrate upregulation of LAG-3 gene and protein expression during demyelination. Furthermore, LAG-3 gene expression coincides with MHCII gene upregulation within the demyelinating lesion. We also demonstrate LAG-3 expression is localized to immature oligodendrocyte progenitor cells (OPCs) and astrocytes. Analyses of LAG-3-/- mice exposed to cuprizone showed an increased depletion of mature oligodendrocytes and an accelerated rate of demyelination. However, OPCs and astrocytes, as well as microglia/macrophages, responded robustly, and during repair, there was a greater number of differentiating mature oligodendrocytes even though remyelination appeared normal. Thus, we have found two novel observations: LAG- 3 is expressed on OPCs and astrocytes, and LAG-3 appears to negatively regulate OPCs during remyelination. These studies suggest that IL-1β and LAG-3 may have significant regulatory effects on glial populations in the central nervous system. Furthermore, the presence of LAG-3 and MHCII in the demyelinating lesion suggests that a direct interaction of OPCs and microglia is plausible.
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  • Matsushima, Glenn
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