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      MiRNA-210 induces microglial activation and regulates microglia-mediated neuroinflammation in neonatal hypoxic-ischemic encephalopathy

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          Abstract

          Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy (HIE). However, the immunological mechanisms that underlie HIE remain unclear. MicroRNA-210 (miR-210) is the master “hypoxamir” and plays a key role in hypoxic-ischemic tissue damage. Herein, we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia. Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE. We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1, thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity. Thus, our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE, highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.

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          MicroRNAs: genomics, biogenesis, mechanism, and function.

          MicroRNAs (miRNAs) are endogenous approximately 22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
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            Neurotoxic reactive astrocytes are induced by activated microglia

            A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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              Identification of a Unique TGF-β Dependent Molecular and Functional Signature in Microglia

              Microglia are myeloid cells of the central nervous system (CNS) that participate both in normal CNS function and disease. We investigated the molecular signature of microglia and identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia vs. myeloid and other immune cells. Out of 239 genes, 106 were enriched in microglia as compared to astrocytes, oligodendrocytes and neurons. This microglia signature was not observed in microglial lines or in monocytes recruited to the CNS and was also observed in human microglia. Based on this signature, we found a crucial role for TGF-β in microglial biology that included: 1) the requirement of TGF-β for the in vitro development of microglia that express the microglial molecular signature characteristic of adult microglia; and 2) the absence of microglia in CNS TGF-β1 deficient mice. Our results identify a unique microglial signature that is dependent on TGF-β signaling which provides insights into microglial biology and the possibility of targeting microglia for the treatment of CNS disease.
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                Author and article information

                Contributors
                boli@llu.edu
                lzhang@llu.edu
                Journal
                Cell Mol Immunol
                Cell Mol Immunol
                Cellular and Molecular Immunology
                Nature Publishing Group UK (London )
                1672-7681
                2042-0226
                12 July 2019
                September 2020
                : 17
                : 9
                : 976-991
                Affiliations
                GRID grid.43582.38, ISNI 0000 0000 9852 649X, Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, , Loma Linda University School of Medicine, ; Loma Linda, CA 92350 USA
                Article
                257
                10.1038/s41423-019-0257-6
                7608107
                31300734
                a02af6db-4c15-4c07-a9c3-10026ab28e74
                © CSI and USTC 2019

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 10 December 2018
                : 13 June 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: NS103017; HL118861
                Award ID: HL118861
                Award ID: NS103017
                Award Recipient :
                Categories
                Article
                Custom metadata
                © CSI and USTC 2020

                Immunology
                neuroinflammation,neonatal hypoxic-ischemic encephalopathy,microrna-210,microglial activation,sirt1,neuroimmunology,mechanisms of disease

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