Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury.
Identifieur interne : 000154 ( Main/Exploration ); précédent : 000153; suivant : 000155Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury.
Auteurs : Masataka Ifuku [Allemagne, Japon] ; Lukas Hinkelmann [Allemagne] ; Leonard D. Kuhrt [Allemagne] ; Ibrahim E. Efe [Allemagne] ; Victor Kumbol [Allemagne] ; Alice Buonfiglioli [Allemagne] ; Christina Krüger [Allemagne] ; Philipp Jordan [Allemagne] ; Marcus Fulde [Allemagne] ; Mami Noda [Japon] ; Helmut Kettenmann [Allemagne] ; Seija Lehnardt [Allemagne]Source :
- Acta neuropathologica communications [ 2051-5960 ] ; 2020.
Abstract
Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5-/- mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS.
DOI: 10.1186/s40478-020-01031-3
PubMed: 32912327
PubMed Central: PMC7488138
Affiliations:
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Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Buonfiglioli, Alice" sort="Buonfiglioli, Alice" uniqKey="Buonfiglioli A" first="Alice" last="Buonfiglioli">Alice Buonfiglioli</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kruger, Christina" sort="Kruger, Christina" uniqKey="Kruger C" first="Christina" last="Krüger">Christina Krüger</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Jordan, Philipp" sort="Jordan, Philipp" uniqKey="Jordan P" first="Philipp" last="Jordan">Philipp Jordan</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Fulde, Marcus" sort="Fulde, Marcus" uniqKey="Fulde M" first="Marcus" last="Fulde">Marcus Fulde</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Noda, Mami" sort="Noda, Mami" uniqKey="Noda M" first="Mami" last="Noda">Mami Noda</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka</wicri:regionArea><orgName type="university">Université de Kyūshū</orgName><placeName><settlement type="city">Fukuoka</settlement><region type="province">Kyūshū</region><region type="prefecture">Préfecture de Fukuoka</region></placeName></affiliation></author><author><name sortKey="Kettenmann, Helmut" sort="Kettenmann, Helmut" uniqKey="Kettenmann H" first="Helmut" last="Kettenmann">Helmut Kettenmann</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Lehnardt, Seija" sort="Lehnardt, Seija" uniqKey="Lehnardt S" first="Seija" last="Lehnardt">Seija Lehnardt</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32912327</idno><idno type="pmid">32912327</idno><idno type="doi">10.1186/s40478-020-01031-3</idno><idno type="pmc">PMC7488138</idno><idno type="wicri:Area/Main/Corpus">000026</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000026</idno><idno type="wicri:Area/Main/Curation">000026</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000026</idno><idno type="wicri:Area/Main/Exploration">000026</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury.</title><author><name sortKey="Ifuku, Masataka" sort="Ifuku, Masataka" uniqKey="Ifuku M" first="Masataka" last="Ifuku">Masataka Ifuku</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="1"><nlm:affiliation>Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa</wicri:regionArea><wicri:noRegion>Fujisawa</wicri:noRegion></affiliation></author><author><name sortKey="Hinkelmann, Lukas" sort="Hinkelmann, Lukas" uniqKey="Hinkelmann L" first="Lukas" last="Hinkelmann">Lukas Hinkelmann</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kuhrt, Leonard D" sort="Kuhrt, Leonard D" uniqKey="Kuhrt L" first="Leonard D" last="Kuhrt">Leonard D. Kuhrt</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Efe, Ibrahim E" sort="Efe, Ibrahim E" uniqKey="Efe I" first="Ibrahim E" last="Efe">Ibrahim E. Efe</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kumbol, Victor" sort="Kumbol, Victor" uniqKey="Kumbol V" first="Victor" last="Kumbol">Victor Kumbol</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Buonfiglioli, Alice" sort="Buonfiglioli, Alice" uniqKey="Buonfiglioli A" first="Alice" last="Buonfiglioli">Alice Buonfiglioli</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Kruger, Christina" sort="Kruger, Christina" uniqKey="Kruger C" first="Christina" last="Krüger">Christina Krüger</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Jordan, Philipp" sort="Jordan, Philipp" uniqKey="Jordan P" first="Philipp" last="Jordan">Philipp Jordan</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Fulde, Marcus" sort="Fulde, Marcus" uniqKey="Fulde M" first="Marcus" last="Fulde">Marcus Fulde</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität Berlin, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität Berlin, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Noda, Mami" sort="Noda, Mami" uniqKey="Noda M" first="Mami" last="Noda">Mami Noda</name><affiliation wicri:level="4"><nlm:affiliation>Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka</wicri:regionArea><orgName type="university">Université de Kyūshū</orgName><placeName><settlement type="city">Fukuoka</settlement><region type="province">Kyūshū</region><region type="prefecture">Préfecture de Fukuoka</region></placeName></affiliation></author><author><name sortKey="Kettenmann, Helmut" sort="Kettenmann, Helmut" uniqKey="Kettenmann H" first="Helmut" last="Kettenmann">Helmut Kettenmann</name><affiliation wicri:level="3"><nlm:affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Lehnardt, Seija" sort="Lehnardt, Seija" uniqKey="Lehnardt S" first="Seija" last="Lehnardt">Seija Lehnardt</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation><affiliation wicri:level="3"><nlm:affiliation>Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author></analytic><series><title level="j">Acta neuropathologica communications</title><idno type="eISSN">2051-5960</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5<sup>-/-</sup> mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">32912327</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>19</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2051-5960</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>1</Issue><PubDate><Year>2020</Year><Month>09</Month><Day>10</Day></PubDate></JournalIssue><Title>Acta neuropathologica communications</Title><ISOAbbreviation>Acta Neuropathol Commun</ISOAbbreviation></Journal><ArticleTitle>Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury.</ArticleTitle><Pagination><MedlinePgn>159</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1186/s40478-020-01031-3</ELocationID><Abstract><AbstractText>Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5<sup>-/-</sup> mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ifuku</LastName><ForeName>Masataka</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hinkelmann</LastName><ForeName>Lukas</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kuhrt</LastName><ForeName>Leonard D</ForeName><Initials>LD</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Efe</LastName><ForeName>Ibrahim E</ForeName><Initials>IE</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kumbol</LastName><ForeName>Victor</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Buonfiglioli</LastName><ForeName>Alice</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krüger</LastName><ForeName>Christina</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jordan</LastName><ForeName>Philipp</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fulde</LastName><ForeName>Marcus</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität Berlin, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Noda</LastName><ForeName>Mami</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kettenmann</LastName><ForeName>Helmut</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lehnardt</LastName><ForeName>Seija</ForeName><Initials>S</Initials><Identifier Source="ORCID">0000-0002-1068-7112</Identifier><AffiliationInfo><Affiliation>Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. seija.lehnardt@charite.de.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>09</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Acta Neuropathol Commun</MedlineTA><NlmUniqueID>101610673</NlmUniqueID><ISSNLinking>2051-5960</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">Chemotaxis</Keyword><Keyword MajorTopicYN="Y">Cytokines</Keyword><Keyword MajorTopicYN="Y">Microglia</Keyword><Keyword MajorTopicYN="Y">Neuronal apoptosis</Keyword><Keyword MajorTopicYN="Y">PI3K/Akt/mTORC1 signaling</Keyword><Keyword MajorTopicYN="Y">Phagocytosis</Keyword><Keyword MajorTopicYN="Y">Toll-like receptor 5</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>07</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>08</Month><Day>29</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>9</Month><Day>11</Day><Hour>5</Hour><Minute>32</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>9</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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last="Ifuku">Masataka Ifuku</name></region><name sortKey="Buonfiglioli, Alice" sort="Buonfiglioli, Alice" uniqKey="Buonfiglioli A" first="Alice" last="Buonfiglioli">Alice Buonfiglioli</name><name sortKey="Buonfiglioli, Alice" sort="Buonfiglioli, Alice" uniqKey="Buonfiglioli A" first="Alice" last="Buonfiglioli">Alice Buonfiglioli</name><name sortKey="Efe, Ibrahim E" sort="Efe, Ibrahim E" uniqKey="Efe I" first="Ibrahim E" last="Efe">Ibrahim E. 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