Abstract
MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45low, major histocompatibility complex (MHC) class IIlow phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.
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Acknowledgements
We thank V. Kuchroo and F.J. Quintana for critical discussion of the results and I. Sotnikov for technical assistance with immunohistochemistry. 2D2 mice were kindly provided by V. Kuchroo (Brigham and Women's Hospital, Harvard Medical School). This work was supported in part by US National Institutes of Health grant R01 NS071039-01A1.
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E.D.P. performed all flow-cytometry assays, EAE experiments, experiments with chimeric, knockout and transgenic mice, in vivo injections of oligonucleotides, cell isolations, cell cultures, coculture assays and immunohistochemistry; collected and analyzed the data; and wrote the manuscript. T.V. performed in vitro transfections, miRNA and mRNA expression assays and data analysis, western blots, luciferase target validation assay, immunohistochemistry and in silico target prediction analysis and helped to write the manuscript. N.B. performed imaging cytometry. E.D.P. and A.M.K. conceived the project. E.D.P., T.V. and A.M.K. developed the hypothesis and designed the experiments. A.M.K. and H.L.W. discussed the hypothesis, helped with data interpretation, coordinated and directed the project and wrote the manuscript.
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Ponomarev, E., Veremeyko, T., Barteneva, N. et al. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway. Nat Med 17, 64–70 (2011). https://doi.org/10.1038/nm.2266
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DOI: https://doi.org/10.1038/nm.2266
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