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      Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

      1 , 1 , 1 , 2 , 1 , 3

      Science Signaling

      American Association for the Advancement of Science (AAAS)

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          Abstract

          The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

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          Most cited references 31

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          Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

          Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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            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.
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              Microglia and macrophages in brain homeostasis and disease

              Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.
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                Author and article information

                Contributors
                Journal
                Science Signaling
                Sci. Signal.
                American Association for the Advancement of Science (AAAS)
                1945-0877
                1937-9145
                April 07 2020
                April 07 2020
                April 07 2020
                April 07 2020
                : 13
                : 626
                : eaay5686
                Affiliations
                [1 ]Pittsburgh Institute of Brain Disorders and Recovery, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
                [2 ]Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
                [3 ]Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15261, USA.
                Article
                10.1126/scisignal.aay5686
                © 2020

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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