Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury
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 incl...
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doaj-5153a1d9c12646a1a2d9ffc007f728792020-11-25T03:54:58ZengBMCActa Neuropathologica Communications2051-59602020-09-018111910.1186/s40478-020-01031-3Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injuryMasataka Ifuku0Lukas Hinkelmann1Leonard D. Kuhrt2Ibrahim E. Efe3Victor Kumbol4Alice Buonfiglioli5Christina Krüger6Philipp Jordan7Marcus Fulde8Mami Noda9Helmut Kettenmann10Seija Lehnardt11Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationInstitute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationCellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationInstitute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationInstitute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthCellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationInstitute of Microbiology and Epizootics, Centre for Infection Medicine, Freie Universität BerlinLaboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu UniversityCellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz AssociationInstitute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthAbstract 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.http://link.springer.com/article/10.1186/s40478-020-01031-3Toll-like receptor 5MicrogliaPI3K/Akt/mTORC1 signalingCytokinesPhagocytosisChemotaxis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masataka Ifuku Lukas Hinkelmann Leonard D. Kuhrt Ibrahim E. Efe Victor Kumbol Alice Buonfiglioli Christina Krüger Philipp Jordan Marcus Fulde Mami Noda Helmut Kettenmann Seija Lehnardt |
spellingShingle |
Masataka Ifuku Lukas Hinkelmann Leonard D. Kuhrt Ibrahim E. Efe Victor Kumbol Alice Buonfiglioli Christina Krüger Philipp Jordan Marcus Fulde Mami Noda Helmut Kettenmann Seija Lehnardt Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury Acta Neuropathologica Communications Toll-like receptor 5 Microglia PI3K/Akt/mTORC1 signaling Cytokines Phagocytosis Chemotaxis |
author_facet |
Masataka Ifuku Lukas Hinkelmann Leonard D. Kuhrt Ibrahim E. Efe Victor Kumbol Alice Buonfiglioli Christina Krüger Philipp Jordan Marcus Fulde Mami Noda Helmut Kettenmann Seija Lehnardt |
author_sort |
Masataka Ifuku |
title |
Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
title_short |
Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
title_full |
Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
title_fullStr |
Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
title_full_unstemmed |
Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
title_sort |
activation of toll-like receptor 5 in microglia modulates their function and triggers neuronal injury |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-09-01 |
description |
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. |
topic |
Toll-like receptor 5 Microglia PI3K/Akt/mTORC1 signaling Cytokines Phagocytosis Chemotaxis |
url |
http://link.springer.com/article/10.1186/s40478-020-01031-3 |
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