title: Differential roles of microglia and monocytes in the inflamed central nervous system.
abstract: In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamasaki
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
authors.forename: Oleg
authors.initials: O
authors.lastname: Butovsky
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ohno
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rietsch
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
authors.forename: Ron
authors.initials: R
authors.lastname: Cialic
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Wu
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Camille E
authors.initials: CE
authors.lastname: Doykan
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lin
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Cotleur
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Grahame
authors.initials: G
authors.lastname: Kidd
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey.
authors.forename: Musab M
authors.initials: MM
authors.lastname: Zorlu
authors.affiliation: Vanderbilt University, Nashville, TN 37235.
authors.forename: Nathan
authors.initials: N
authors.lastname: Sun
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058 Zhejiang, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: LiPing
authors.initials: L
authors.lastname: Liu
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Jar-Chi
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Taylor
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Ohio State University College of Medicine, Columbus, OH 43210.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Uehlein
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44106.
authors.forename: Debra
authors.initials: D
authors.lastname: Dixon
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Gu
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Baylor University, Waco, TX 77030.
authors.forename: Crina M
authors.initials: CM
authors.lastname: Floruta
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute; Department of Quantitative Health Sciences; and Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44106 Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44106 ransohr@ccf.org.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D048430:Cell Shape; D002490:Central Nervous System / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D007700:Kinetics; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology* / Q000648:ultrastructure; D009000:Monocytes / Q000473:pathology* / Q000648:ultrastructure; D011901:Ranvier's Nodes / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515335:Ccr2 protein, mouse; C471885:Cx3cr1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine