ABSTRACT
The pathology in neurodegenerative diseases is often accompanied by inflammation. It is well-known that many cells within the central nervous system (CNS) also contribute to ongoing neuroinflammation, which can promote neurodegeneration. Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease in which there is a complex interplay between resident CNS cells to mediate myelin and axonal damage, and this communication network can vary depending on the subtype and chronicity of disease. Oligodendrocytes, the myelinating cell of the CNS, and their precursors, oligodendrocyte precursor cells (OPCs), are often thought of as the targets of autoimmune pathology during MS and in several animal models of MS; however, there is emerging evidence that OPCs actively contribute to inflammation that directly and indirectly contributes to neurodegeneration. Here we discuss several contributors to MS disease progression starting with lesion pathology and murine models amenable to studying particular aspects of disease. We then review how OPCs themselves can play an active role in promoting neuroinflammation and neurodegeneration, and how other resident CNS cells including microglia, astrocytes, and neurons can impact OPC function. Further, we outline the very complex and pleiotropic role(s) of several inflammatory cytokines and other secreted factors classically described as solely deleterious during MS and its animal models, but in fact, have many neuroprotective functions and promote a return to homeostasis, in part via modulation of OPC function. Finally, since MS affects patients from the onset of disease throughout their lifespan, we discuss the impact of aging on OPC function and CNS recovery. It is becoming clear that OPCs are not simply a bystander during MS progression and uncovering the active roles they play during different stages of disease will help uncover potential new avenues for therapeutic intervention.
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 has protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Here, we demonstrate that IFNγ signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity. METHODS: In a multiple sclerosis (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 reverse transcription-polymerase chain reaction (qRT-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. Central nervous system (CNS) tissues were analyzed by immunohistochemistry (IHC) and immunofluorescence, and cell-specific colocalization was quantified. RESULTS: In MS tissue, iP expression was enhanced in the 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 the disease and led to increased oxidative stress and poly-ubiquitinated protein buildup. 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 in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.
