let-7 MicroRNAs Regulate Microglial Function and Suppress Glioma Growth through Toll-Like Receptor 7

Alice Buonfiglioli; Ibrahim E Efe; Dilansu Guneykaya; Andranik Ivanov; Yimin Huang; Elisabeth Orlowski; Christina Krüger; Rudolf A Deisz; Darko Markovic; Charlotte Flüh; Andrew G Newman; Ulf C Schneider; Dieter Beule; Susanne A Wolf; Omar Dzaye; David H Gutmann; Marcus Semtner; Helmut Kettenmann; Seija Lehnardt

doi:10.1016/j.celrep.2019.11.029

let-7 MicroRNAs Regulate Microglial Function and Suppress Glioma Growth through Toll-Like Receptor 7

Cell Rep. 2019 Dec 10;29(11):3460-3471.e7. doi: 10.1016/j.celrep.2019.11.029.

Authors

Alice Buonfiglioli¹, Ibrahim E Efe², Dilansu Guneykaya³, Andranik Ivanov⁴, Yimin Huang³, Elisabeth Orlowski³, Christina Krüger⁵, Rudolf A Deisz⁵, Darko Markovic⁶, Charlotte Flüh⁷, Andrew G Newman⁵, Ulf C Schneider⁸, Dieter Beule⁹, Susanne A Wolf¹⁰, Omar Dzaye¹¹, David H Gutmann¹², Marcus Semtner³, Helmut Kettenmann¹³, Seija Lehnardt¹⁴

Affiliations

¹ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
² Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Department of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
³ Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
⁴ Core Unit Bioinformatics, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
⁵ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
⁶ Department of Neurosurgery, Helios Clinics, 13125 Berlin, Germany.
⁷ Department of Neurosurgery, University Medical Center Schleswig-Holstein (UKSH), 24105 Kiel, Germany.
⁸ Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
⁹ Core Unit Bioinformatics, Berlin Institute of Health, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
¹⁰ Department of Ophthalmology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
¹¹ Department of Radiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany. Electronic address: kettenmann@mdc-berlin.de.
¹⁴ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany. Electronic address: seija.lehnardt@charite.de.

PMID: 31825829
DOI: 10.1016/j.celrep.2019.11.029

Abstract

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma.

Keywords: Toll-like receptor 7; glioblastoma; lethal-7; microRNA; microglia.

MeSH terms

Animals
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Line, Tumor
Cells, Cultured
Female
Gene Expression Regulation, Neoplastic
Glioma / genetics*
Glioma / metabolism
Glioma / pathology
Humans
Male
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Microglia / metabolism*
Signal Transduction
Toll-Like Receptor 7 / genetics*
Toll-Like Receptor 7 / metabolism

Substances

MicroRNAs
TLR7 protein, human
Toll-Like Receptor 7
mirnlet7 microRNA, human