ORIGINAL RESEARCH article
Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1645062
Extracellular microRNAs modulate human microglial function through TLR8
Provisionally accepted
Hannah Weidling1
Edyta Motta2
Leonard D Kuhrt2Christina Krüger1
Caio Andreeta Figueiredo2Thomas Wallach1
Silke Frahm2
Sebastian Diecke2
Susanne Wolf1Helmut Kettenmann2*
Seija Lehnardt1*- 1Charité University Medicine Berlin, Berlin, Germany
- 2Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, Buch, Germany
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Objective: MicroRNAs (miRNAs) are abundantly expressed in the brain and are specifically dysregulated in central nervous system diseases. They act as post-transcriptional gene regulators but can a l s o serve as ligands for Toll-like receptors (TLRs). This study aims to investigate disease-associated miRNAs as signaling molecules for human microglia. Methods: Using a machine learning algorithm and the disease-linked database PhenoMiR, we identified Alzheimer's disease (AD)- and glioma-associated miRNAs as ligands for TLR7 and T L R 8. Expression of human TLR7 and TLR8 in iPSC-derived human microglia-like cells (iMGLs) was validated by RT-qPCR. Using ELISA, scratch assay, and FACS, we investigated the miRNAs' potential to modulate iMGL function, including cytokine release, motility, and phagocytosis, respectively. The selective human TLR8 antagonist CPT-CU9a was used to determine the role of this receptor in miRNA-induced modulation of human microglial activity. Co-cultures of IMGLs and iPSC-derived human cortical neurons (iNeurons) were analyzed by Neurotrack imaging to assess the effects of miRNAs on human neuronal neurites. Results: We identified AD-and glioma-associated miR-9-5p, miR-132-5p, miR-340-3p, miR-30e-3p, miR-501-3p, and let-7b as ligands for human TLR7 and TLR8. Exposure of iMGLs to select miRNAs, including miR-9-5p, miR-132-5p, and miR-340-3p, led to interleukin-6 (IL-6) and tumor necrosis factor (TNF) mRNA expression and protein release in a sequence-dependent fashion. Also, these miRNAs acting, as signaling molecules, modulated iMGL motility and phagocytosis activity. The miRNA-induced effects on iMGLs were abolished by CPT-CU9a.
Keywords: extracellular microRNA, Human microglia, microglial function Toll-like Receptor 8, Stem Cells, IPSC, Alzheimer's disease, Glioma
Received: 11 Jun 2025; Accepted: 23 Oct 2025.
Copyright: © 2025 Weidling, Motta, Kuhrt, Krüger, Andreeta Figueiredo, Wallach, Frahm, Diecke, Wolf, Kettenmann and Lehnardt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Helmut Kettenmann, kettenmann@mdc-berlin.de
Seija Lehnardt, seija.lehnardt@charite.de
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