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Abstract
BackgroundIn 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.MethodsIn 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.ResultsIn 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.ConclusionsTaken 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.
Highlights
Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) [1]
The iP is expressed in regional astrocytes within multiple sclerosis (MS) lesions and is associated with reduced oxidative stress In several neurodegenerative diseases, the iP is known to clear reactive oxygen species (ROS) and degrade poly-ubiquitinated proteins [69,70,71], and there is evidence that the iP may be dysregulated during MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS [71,72,73]
We found PSMB7 to be significantly downregulated while PSMB8 was significantly increased in white matter lesions (WML) compared to controls and normal-appearing white matter (NAWM; Fig. 1a, b)
Summary
Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) [1]. Relapsing-remitting MS (RRMS) is a subtype that affects approximately 85% of patients and is characterized by episodic periods of neurological dysfunction, often associated with inflammation, followed by partial or complete recovery. Primary progressive MS (PPMS), a third subtype of MS, affects approximately 15% of patients and is associated with continuous, progressive loss of neurological function after initial diagnosis, without periods of remission [5, 6]. It is thought that the pathology associated with RRMS has a significant inflammatory component, while in SPMS and PPMS, inflammation is relatively limited [6]. We demonstrate that IFNγ signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity
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