MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway.
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 CD45(low), major histocompatibility complex (MHC) class II(low) 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.
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Eugene D
ED
Ponomarev
Tatyana
T
Veremeyko
Natasha
N
Barteneva
Anna M
AM
Krichevsky
Howard L
HL
Weiner
D000818:Animals; D001921:Brain / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D017628:Microglia / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D009474:Neurons / Q000502:physiology; D051381:Rats
D022762:CCAAT-Enhancer-Binding Proteins; C509207:MIRN124 microRNA, human; C548144:MIRN124 microRNA, rat; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse