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

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 IFNß 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.

The Emerging Role of the Cannabinoid Receptor Family in Peripheral and Neuro-immune Interactions.

The classical endogenous cannabinoid (CB) system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) and their G-protein coupled receptors (GPCR), CB1 and CB2 which together constitutes the endocannabinoid system (ECS). However, putative, novel lipid-sensing CB receptors have recently been identified, including the orphan GPR55 and GPR18 receptors that are regulated by cannabinoid-like molecules and interact with CB system. CB receptors and associated orphan GPCRs are expressed at high levels in the immune and/or central nervous systems (CNS) and regulate a number of neurophysiological processes, including key events involved in neuroinflammation. As such, these receptors have been identified as emerging therapeutic targets for a number of brain disorders in which neuroinflammation is a key feature, including multiple sclerosis (MS) and Alzheimer's disease (AD). This review will consider the role of the wider cannabinoid receptor superfamily in mediating immune function with a focus on the immune processes that contribute to neuroinflammatory conditions.