Innate Immune Responses in Human Oligodendrocytes

• Author / Creator

  Saito, Leina Bernadette

• The central nervous system (CNS) is comprised by the brain, spinal cord, and optic nerves, which are vital for normal bodily functions. Microglia and astrocytes are the CNS cells that contribute to homeostasis although excessive immune activation of these cells leads to pathogenic neuroinflammation including inflammasome induction and associated neurodegeneration that are observed in diseases such as multiple sclerosis (MS). Inflammasomes are cytosolic protein complexes that serve as both sensors and effectors of innate immunity through enabling caspase-1 activation with ensuing cytokine release and/or inflammatory programmed cell death, termed pyroptosis. In MS, demyelination and axonal transection occurs in conjunction with glial activation, and infiltrating (and activated) leukocytes. Oligodendrocytes are the myelin-forming cells of the CNS and are injured in MS although their participation in inflammation is uncertain. Nonetheless, oligodendrocytes contain the molecular machinery to respond to proinflammatory stimuli, and because of their central role in MS pathogenesis, it was critical to determine if oligodendrocytes contribute to neuroinflammation. Thus, the capacity of cultured mature and immature human oligodendrocytes to express innate immune molecules and their concurrent vulnerability to injury and cell death were investigated. The ability of in vivo oligodendrocytes to respond to inflammation in a toxic model of demyelination in mice was subsequently examined. TNFα exposure induced expression of inflammasome- and Type I interferon (IFN)-associated genes in cultured mature human progenitor-derived oligodendrocytes (PDOs). Type I IFN bioactivity was detected in supernatants, although prototypic inflammasome cytokines IL-1β and IL-18 were not released, from TNFα-exposed or JC virus-infected PDOs. Caspase-1 and the executioner protein, gasdermin D immunoreactivity were increased in TNFα-exposed mature PDOs. Treatment with the caspase-1 inhibitor, VX-765, suppressed gasdermin D immunoreactivity and prevented pyroptosis in TNFα-exposed PDOs. Demyelination of the corpus callosum with accompanying glial activation and axonal disruption were observed in mice after four and six weeks of cuprizone exposure. Intranasal VX-765 treatment of cuprizone-exposed animals prevented myelin basic protein loss, and both microglial and astrocytic activation in the corpus callosum. While cuprizone-exposed mice displayed gasdermin D immunopositive oligodendrocytes, VX-765 treatment selectively suppressed oligodendrocyte progenitor cell induction in the corpus callosum and prevented axonal injury. Overall, activated human oligodendrocytes displayed innate immune responses in a differentiation-state dependent manner, with evidence of pyroptosis. Caspase-1 and gasdermin D induction was apparent in cuprizone-mediated CNS demyelination. These results demonstrate oligodendrocytes are immunologically active and contribute to CNS innate immunity that could affect cell survival. Intranasal delivery of VX-765 was selectively neuroprotective and highlighted new therapeutic options for inflammatory demyelinating disorders of the CNS such as MS.

• Subjects / Keywords

  • oligodendrocytes
  • innate immune responses

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-119j-zq43

• License

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