MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway

By E. Ponomarev, Tatyana Veremeyko, N. Barteneva, Anna M. Krichevsky, Howard L. Weiner. Nature Medicine, 2010

816 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/201a8fce4fc51465ff93360ee1e1b291babf5337

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Citations in the corpus

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, result): “…predicted TF target genes of hsa-miR-124, six ( TEAD1 , CEBPA , AR , SP1 , SNAI2 , NFATC1 ) are supported by independent experimental evidence (Lim et al. 2005; Baek et al. 2008; Ponomarev et al. 2011; Liang et al. 2013; Shi et al. 2013), againconfirmingthehighaccuracyofISMARA’stargetpredictions.”
Alternatively activated microglia and macrophages in the central nervous system. (2015, background): “On the other hand, the best characterized anti-inflammatory miRNA, miRNA124, is expressed both in microglia and macrophages in normal conditions or during disease recovery while CNS it is downregulated during active inflammation in the (Ponomarev et al., 2011).”
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “1 levels through miR124 overexpression can decrease expression of TNF-α, iNOS and MHC-II, thereby suppressing neuroinflammatory response in macrophages [491].”
Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance (2014, background): “(91) found that miR-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages in a C/EBPα-PU.”
Macrophage phenotypes in atherosclerosis (2014, background): “Likewise, miR-124, a brain-specific miRNA expressed in microglia (133), drives macrophage polarization toward a M2 phenotype in mice (133).”
The biphasic function of microglia in ischemic stroke (2017, positive): “Intracerebral injection of IL-4 or IL-13 in the brain enhanced Arginase-1, Ym1, CD206 expression (Girard et al., 2013), supporting that IL-4 and IL-13 could promote microglia polarization into M2a phenotype.”
microRNA regulation of inflammatory responses. (2012, neutral): “miR-124a also affects EAE in mice (74).”
Macrophages: development and tissue specialization. (2015, background): “Neuronal CX3CL1, CD200, and exosome-derived miR-124 were shown to control microglial cell-autonomous neurotoxicity in various CNS inflammation models (132, 133, 182).”