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Microglial Interferon Signaling and White Matter

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Abstract

Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood–brain barrier integrity. All of these IFN-induced effects result in numerous downstream consequences on white matter pathology and microglial reactivity. Dysregulation of IFN signaling in mouse models with genetic deficiency in ubiquitin specific protease 18 (USP18) leads to a severe neurological phenotype and neuropathological changes that include white matter microgliosis and pro-inflammatory gene expression in dystrophic microglia. A class of genetic disorders in humans, referred to as pseudo-TORCH syndrome (PTS) for the clinical resemblance to infection-induced TORCH syndrome, also show dysregulation of IFN signaling, which leads to severe neurological developmental disease. In these disorders, the excessive activation of IFN signaling during CNS development results in a destructive interferonopathy with similar induction of microglial dysfunction as seen in USP18 deficient mice. Other recent studies implicate “microgliopathies” more broadly in neurological disorders including Alzheimer’s disease (AD) and MS, suggesting that microglia are a potential therapeutic target for disease prevention and/or treatment, with interferon signaling playing a key role in regulating the microglial phenotype.

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Acknowledgements

We thank Dorender Dankwa for her assistance with microglial cultures and ELISA analysis. This manuscript was funded by NIH F32NS100245 (A.M.) and NIH R01NS076620 (J.R.W.).

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  1. Department of Neurology, University of Washington, Seattle, WA, 98195, USA

    Ashley McDonough, Richard V. Lee & Jonathan R. Weinstein

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McDonough, A., Lee, R.V. & Weinstein, J.R. Microglial Interferon Signaling and White Matter. Neurochem Res 42, 2625–2638 (2017). https://doi.org/10.1007/s11064-017-2307-8

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