Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury
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RESEARCH
Activation of Toll‑like receptor 5 in microglia modulates their function and triggers neuronal injury Masataka Ifuku1,7†, Lukas Hinkelmann2†, Leonard D. Kuhrt1,3, Ibrahim E. Efe1,3, Victor Kumbol2, Alice Buonfiglioli1,2, Christina Krüger2, Philipp Jordan1, Marcus Fulde4, Mami Noda5, Helmut Kettenmann1† and Seija Lehnardt2,6*†
Abstract Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogenand 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. Keywords: Toll-like receptor 5, Microglia, PI3K/Akt/mTORC1 signaling, Cytokines, Phagocytosis, Chemotaxis, Neuronal apoptosis Background Toll-like receptors (TLRs) are pattern recognition receptors that are activated by both pathogen- and hostderived, potentially damage-associated, molecular patterns [61]. Engagement of these membrane receptors in the brain can result in various outcomes, such as *Correspondence: [email protected] † Masataka Ifuku, Lukas Hinkelmann, Helmut Kettenmann, Seija Lehnardt contributed equally. 2 Institute of Cell Biology and Neurobiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, HumboldtUniversität zuBerlin, and Berlin Institute of Health, Berlin, Germany Full list of author information is available at the end of the article
chronic inflammation, neuronal injury, either in a cellautonomous or inflammation-associated fashion, or in regenerative processes [36, 40, 57]. Among the 13 members of the TLR family in mouse and human characterized to date, TLR5 is the only protein-binding TLR that is conserved in vertebrates from fish to mammals, and specifically recognizes flagellin, a fibrillar protein derived from bacteria [22, 31, 59].
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