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CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis

BACKGROUND: Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in t...

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Autores principales: Funk, Kristen E., Klein, Robyn S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354430/
https://www.ncbi.nlm.nih.gov/pubmed/30704498
http://dx.doi.org/10.1186/s12974-019-1397-4
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author Funk, Kristen E.
Klein, Robyn S.
author_facet Funk, Kristen E.
Klein, Robyn S.
author_sort Funk, Kristen E.
collection PubMed
description BACKGROUND: Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. METHODS: The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. RESULTS: Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. CONCLUSIONS: Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1397-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-63544302019-02-07 CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis Funk, Kristen E. Klein, Robyn S. J Neuroinflammation Research BACKGROUND: Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. METHODS: The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. RESULTS: Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. CONCLUSIONS: Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1397-4) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-31 /pmc/articles/PMC6354430/ /pubmed/30704498 http://dx.doi.org/10.1186/s12974-019-1397-4 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Funk, Kristen E.
Klein, Robyn S.
CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title_full CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title_fullStr CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title_full_unstemmed CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title_short CSF1R antagonism limits local restimulation of antiviral CD8(+) T cells during viral encephalitis
title_sort csf1r antagonism limits local restimulation of antiviral cd8(+) t cells during viral encephalitis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354430/
https://www.ncbi.nlm.nih.gov/pubmed/30704498
http://dx.doi.org/10.1186/s12974-019-1397-4
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