Invited Presentations Invited Abstracts

PS02.01 - Neuroprotective and immunomodulatory effects of astrocytes in chronic EAE

Speakers
  • J. Williams
Authors
  • B. Smith
  • M. Sinyuk
  • J. Jenkins
  • M. Psenicka
  • J. Williams
Presentation Number
PS02.01
Presentation Topic
Invited Presentations
Lecture Time
10:15 - 10:30

Abstract

Abstract

Background: In early autoimmune neuroinflammation, interferon (IFN)γ and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNγ is shown to have protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Further, although MS affects the spinal cord in a majority of MS patients, there is still much to learn regarding its pathology. Here, we demonstrate that IFNγ signaling in spinal cord astrocytes induces the iP and promotes protection of the central nervous system (CNS) during chronic autoimmunity.

Methods: In MS brain, we evaluated mRNA expression and labeled postmortem MS brainstem and spinal cord for iP subunits and indicators of oxidative stress. Primary regional human astrocytes were analyzed for iP regulation and function by quantitative PCR, Western blot, OxyBlot, and reactive oxygen species and caspase activity detection assays. Following immunization with myelin oligodendrocyte glycoprotein (MOG)35-55, the role of IFNγ signaling and the iP during chronic experimental autoimmune encephalomyelitis (EAE) were assessed using pharmacologic inhibition of the iP and genetic interruption of IFNγ signaling specifically in astrocytes. CNS tissues were analyzed by immunofluorescent analysis and cell-specific colocalization was quantified.

Results: In MS tissue, iP expression was enhanced in spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFNγ stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, EAE, ONX 0914 treatment exacerbated disease and led to increased oxidative stress and poly-ubiquitinated protein build-up. Finally, mice with astrocyte-specific loss of the IFNγ receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress and poly-ubiquitinated protein accumulation in astrocytes.

Conclusions: Taken together, our data reveal a protective role for IFNγ signaling in spinal cord astrocytes during chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.

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