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      Cellular and Molecular Characterization of Microglia: A Unique Immune Cell Population

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          Abstract

          Microglia are essential for the development and function of the adult brain. Microglia arise from erythro-myeloid precursors in the yolk sac and populate the brain rudiment early during development. Unlike monocytes that are constantly renewed from bone marrow hematopoietic stem cells throughout life, resident microglia in the healthy brain persist during adulthood via constant self-renewal. Their ontogeny, together with the absence of turnover from the periphery and the singular environment of the central nervous system, make microglia a unique cell population. Supporting this notion, recent genome-wide transcriptional studies revealed specific gene expression profiles clearly distinct from other brain and peripheral immune cells. Here, we highlight the breakthrough studies that, over the last decades, helped elucidate microglial cell identity, ontogeny, and function. We describe the main techniques that have been used for this task and outline the crucial milestones that have been achieved to reach our actual knowledge of microglia. Furthermore, we give an overview of the “microgliome” that is currently emerging thanks to the constant progress in the modern profiling techniques.

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          Most cited references80

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          The Microglial Sensome Revealed by Direct RNA Sequencing

          Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection.
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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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              Control of microglial neurotoxicity by the fractalkine receptor.

              Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 March 2017
                2017
                : 8
                : 198
                Affiliations
                [1] 1NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health , Luxembourg, Luxembourg
                [2] 2Luxembourg Centre for Systems Biomedicine, University of Luxembourg , Esch-Belval, Luxembourg
                [3] 3Department of Psychiatry and Psychotherapy, Section Molecular Psychiatry, University of Freiburg , Freiburg, Germany
                [4] 4Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                Author notes

                Edited by: Fabrice Cognasse, The Rhone-Alpes-Auvergne Regional Branch of the French National Blood System, France

                Reviewed by: Sophie Laye, Centre Bordeaux-Aquitaine (INRA), France; Marie-Eve Tremblay, Laval University, Canada

                *Correspondence: Alessandro Michelucci, alessandro.michelucci@ 123456lih.lu

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00198
                5332364
                28303137
                a8e632a6-3fa9-4828-89db-8c83a120aa5b
                Copyright © 2017 Sousa, Biber and Michelucci.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 November 2016
                : 09 February 2017
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 143, Pages: 17, Words: 12266
                Funding
                Funded by: Fonds National de la Recherche Luxembourg 10.13039/501100001866
                Award ID: 6916713
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Award ID: KNDD, ReelinSys
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: BI 668/5-1, BI 668/2-2
                Categories
                Immunology
                Review

                Immunology
                microglia history,rio hortega,technology,genome-wide,microgliome
                Immunology
                microglia history, rio hortega, technology, genome-wide, microgliome

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