CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis
Identifieur interne : 000268 ( Pmc/Checkpoint ); précédent : 000267; suivant : 000269CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis
Auteurs : Kristen E. Funk [États-Unis] ; Robyn S. Klein [États-Unis]Source :
- Journal of Neuroinflammation [ 1742-2094 ] ; 2019.
Abstract
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.
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.
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.
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.
The online version of this article (10.1186/s12974-019-1397-4) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12974-019-1397-4
PubMed: 30704498
PubMed Central: 6354430
Affiliations:
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PMC:6354430Le document en format XML
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">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.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s12974-019-1397-4) contains supplementary material, which is available to authorized users.</p>
</sec>
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<author><name sortKey="Arinrad, S" uniqKey="Arinrad S">S Arinrad</name>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Neuroinflammation</journal-id>
<journal-id journal-id-type="iso-abbrev">J Neuroinflammation</journal-id>
<journal-title-group><journal-title>Journal of Neuroinflammation</journal-title>
</journal-title-group>
<issn pub-type="epub">1742-2094</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">30704498</article-id>
<article-id pub-id-type="pmc">6354430</article-id>
<article-id pub-id-type="publisher-id">1397</article-id>
<article-id pub-id-type="doi">10.1186/s12974-019-1397-4</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>CSF1R antagonism limits local restimulation of antiviral CD8<sup>+</sup>
T cells during viral encephalitis</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Funk</surname>
<given-names>Kristen E.</given-names>
</name>
<address><email>kristenfunk@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Klein</surname>
<given-names>Robyn S.</given-names>
</name>
<address><email>rklein@wustl.edu</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Internal Medicine, Division of Infectious Diseases,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
Saint Louis, MO 63110 USA</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Pathology and Immunology,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
Saint Louis, MO 63110 USA</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2355 7002</institution-id>
<institution-id institution-id-type="GRID">grid.4367.6</institution-id>
<institution>Department of Neurosciences,</institution>
<institution>Washington University School of Medicine,</institution>
</institution-wrap>
Saint Louis, MO 63110 USA</aff>
</contrib-group>
<pub-date pub-type="epub"><day>31</day>
<month>1</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>31</day>
<month>1</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>16</volume>
<elocation-id>22</elocation-id>
<history><date date-type="received"><day>24</day>
<month>9</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>2</day>
<month>1</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), 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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p id="Par1">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.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">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.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">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.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">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.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s12974-019-1397-4) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>West Nile virus</kwd>
<kwd>Microglia</kwd>
<kwd>Antiviral T cells</kwd>
<kwd>Viral encephalitis</kwd>
<kwd>Colony-stimulating factor 1 receptor</kwd>
<kwd>PLX5622</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>R01 NS052632</award-id>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000002</institution-id>
<institution>National Institutes of Health</institution>
</institution-wrap>
</funding-source>
<award-id>R01 AI101400</award-id>
<award-id>K99 AG053412</award-id>
<principal-award-recipient><name><surname>Funk</surname>
<given-names>Kristen E.</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000124</institution-id>
<institution>Office of Research on Women's Health</institution>
</institution-wrap>
</funding-source>
<award-id>U19 AI083019</award-id>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Missouri (État)</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Missouri (État)"><name sortKey="Funk, Kristen E" sort="Funk, Kristen E" uniqKey="Funk K" first="Kristen E." last="Funk">Kristen E. Funk</name>
</region>
<name sortKey="Klein, Robyn S" sort="Klein, Robyn S" uniqKey="Klein R" first="Robyn S." last="Klein">Robyn S. Klein</name>
<name sortKey="Klein, Robyn S" sort="Klein, Robyn S" uniqKey="Klein R" first="Robyn S." last="Klein">Robyn S. Klein</name>
<name sortKey="Klein, Robyn S" sort="Klein, Robyn S" uniqKey="Klein R" first="Robyn S." last="Klein">Robyn S. Klein</name>
</country>
</tree>
</affiliations>
</record>
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