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

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.

Highlights

Microglia respond to brain pathological states by migrating toward the lesion site, releasing inflammatory molecules, engulfing cell debris (Napoli and Neumann, 2009), and presenting diseaseassociated antigen, thereby contributing to CNS disease pathobiology (Wlodarczyk et al, 2014)
Select Members of the let-7 miRNA Family Activate Microglia via TLR7 Signaling Microglia are the resident immune cells of the CNS, where they function as sensors of changes in their environment caused by invading pathogens and host-derived factors
On the basis of sequence similarity to known TLR7 ligands, such as the oligoribonucleotide ssRNA40 derived from HIV, their abundant expression in the CNS, and their key role in immune responses in pathology including cancer, we focused on the let-7 miRNA family members as potential signaling activators of microglia in health and in the setting of GBM

Summary

Introduction

Microglia respond to brain pathological states by migrating toward the lesion site, releasing inflammatory molecules, engulfing cell debris (Napoli and Neumann, 2009), and presenting diseaseassociated antigen, thereby contributing to CNS disease pathobiology (Wlodarczyk et al, 2014). Some of these responses are mediated by TLRs, such as TLR7, which detects ssRNA (Diebold et al, 2004; Heil et al, 2004) and controls microglial chemotaxis (Ifuku et al, 2016). Glioma-associated microglia and invading peripheral macrophages constitute up to 30% of the tumor tissue, adopting a tumor-supportive phenotype

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