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The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes

BACKGROUND: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with...

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Autores principales: West, Phillip K., McCorkindale, Andrew N., Guennewig, Boris, Ashhurst, Thomas M., Viengkhou, Barney, Hayashida, Emina, Jung, So Ri, Butovsky, Oleg, Campbell, Iain L., Hofer, Markus J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013466/
https://www.ncbi.nlm.nih.gov/pubmed/35429976
http://dx.doi.org/10.1186/s12974-022-02441-x
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author West, Phillip K.
McCorkindale, Andrew N.
Guennewig, Boris
Ashhurst, Thomas M.
Viengkhou, Barney
Hayashida, Emina
Jung, So Ri
Butovsky, Oleg
Campbell, Iain L.
Hofer, Markus J.
author_facet West, Phillip K.
McCorkindale, Andrew N.
Guennewig, Boris
Ashhurst, Thomas M.
Viengkhou, Barney
Hayashida, Emina
Jung, So Ri
Butovsky, Oleg
Campbell, Iain L.
Hofer, Markus J.
author_sort West, Phillip K.
collection PubMed
description BACKGROUND: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. METHODS: Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. RESULTS: We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer’s disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. CONCLUSIONS: Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02441-x.
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spelling pubmed-90134662022-04-18 The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes West, Phillip K. McCorkindale, Andrew N. Guennewig, Boris Ashhurst, Thomas M. Viengkhou, Barney Hayashida, Emina Jung, So Ri Butovsky, Oleg Campbell, Iain L. Hofer, Markus J. J Neuroinflammation Research BACKGROUND: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. METHODS: Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. RESULTS: We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer’s disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. CONCLUSIONS: Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02441-x. BioMed Central 2022-04-16 /pmc/articles/PMC9013466/ /pubmed/35429976 http://dx.doi.org/10.1186/s12974-022-02441-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
West, Phillip K.
McCorkindale, Andrew N.
Guennewig, Boris
Ashhurst, Thomas M.
Viengkhou, Barney
Hayashida, Emina
Jung, So Ri
Butovsky, Oleg
Campbell, Iain L.
Hofer, Markus J.
The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title_full The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title_fullStr The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title_full_unstemmed The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title_short The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
title_sort cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013466/
https://www.ncbi.nlm.nih.gov/pubmed/35429976
http://dx.doi.org/10.1186/s12974-022-02441-x
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