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
Affiliations
Alice Buonfiglioli
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
Ibrahim E. Efe
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
Dilansu Guneykaya
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Andranik Ivanov
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
Yimin Huang
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Elisabeth Orlowski
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Christina Krüger
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
Rudolf A. Deisz
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
Darko Markovic
Department of Neurosurgery, Helios Clinics, 13125 Berlin, Germany
Charlotte Flüh
Department of Neurosurgery, University Medical Center Schleswig-Holstein (UKSH), 24105 Kiel, Germany
Andrew G. Newman
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
Ulf C. Schneider
Department of Neurosurgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Dieter Beule
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
Susanne A. Wolf
Department of Ophthalmology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Omar Dzaye
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
David H. Gutmann
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
Marcus Semtner
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Helmut Kettenmann
Department of Cellular Neurosciences, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Corresponding author
Seija Lehnardt
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; Corresponding author
Summary: 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. : Buonfiglioli et al. elucidate the role of let-7 miRNAs acting as Toll-like receptor (TLR) ligands in the brain. Select let-7 miRNAs function as signaling molecules to modulate diverse microglial functions and glioma growth through TLR7. These data establish let-7 miRNAs as TLR7 signaling activators of microglia in health and glioma. Keywords: glioblastoma, lethal-7, microglia, microRNA, Toll-like receptor 7
