Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression

Autor: Éadaoin W. Griffin, Colm Cunningham, Carol L. Murray, Robert H. Field, Renata Rodrigues dos Reis, Orla Haugh, Ana Belen Lopez-Rodriguez, Lucas Silva Tortorelli, Lei Jin, Donal J. Cox, Ed C. Lavelle, Aisling Dunne, Arshed Nazmi, Edel Hennessy
Rok vydání: 2019
Předmět:
0301 basic medicine
medicine.medical_treatment
microglia
Receptor
Interferon alpha-beta
neuroinflammation
Mice
0302 clinical medicine
cytokine
Research Articles
axon
Mice
Knockout
Mice
Inbred BALB C
Microglia
Neurodegeneration
phagocytosis
Neurodegenerative Diseases
interferon
Phenotype
Cytokine
medicine.anatomical_structure
Neurology
Stimulator of interferon genes
Interferon Type I
lysosome
Disease Progression
Female
medicine.symptom
white matter
Research Article
Inflammation
Biology
prion
03 medical and health sciences
Cellular and Molecular Neuroscience
medicine
Animals
cathepsin
scavenger
Neuroinflammation
Innate immune system
TREM2
scrapie
Membrane Proteins
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
inflammation
Chronic Disease
Immunology
DNA damage
030217 neurology & neurosurgery
STING
Zdroj: Glia
ISSN: 1098-1136
0894-1491
Popis: Type I interferons (IFN‐I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN‐I has been implicated in neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN‐I in murine prion disease (ME7) and examined the contribution of the IFN‐I receptor IFNAR1 to disease progression. The data indicate a robust IFNβ response, specifically in microglia, with evidence of IFN‐dependent genes in both microglia and astrocytes. This IFN‐I response was absent in stimulator of interferon genes (STING−/−) mice. Microglia showed increased numbers and activated morphology independent of genotype, but transcriptional signatures indicated an IFNAR1‐dependent neuroinflammatory phenotype. Isolation of microglia and astrocytes demonstrated disease‐associated microglial induction of Tnfα, Tgfb1, and of phagolysosomal system transcripts including those for cathepsins, Cd68, C1qa, C3, and Trem2, which were diminished in IFNAR1 and STING deficient mice. Microglial increases in activated cathepsin D, and CD68 were significantly reduced in IFNAR1−/− mice, particularly in white matter, and increases in COX‐1 expression, and prostaglandin synthesis were significantly mitigated. Disease progressed more slowly in IFNAR1−/− mice, with diminished synaptic and neuronal loss and delayed onset of neurological signs and death but without effect on proteinase K‐resistant PrP levels. Therefore, STING‐dependent IFN‐I influences microglial phenotype and influences neurodegenerative progression despite occurring secondary to initial degenerative changes. These data expand our mechanistic understanding of IFN‐I induction and its impact on microglial function during chronic neurodegeneration.
Databáze: OpenAIRE
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