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J Exp Med. 2014 Jul 28;211(8):1533-49. doi: 10.1084/jem.20132477. Epub 2014 Jul 7.

Differential roles of microglia and monocytes in the inflamed central nervous system.

Author information

1
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.
2
Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115.
3
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.
4
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.
5
Vanderbilt University, Nashville, TN 37235.
6
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.
7
Case Western Reserve University, School of Medicine, Cleveland, OH 44106.
8
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.
9
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.
10
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, CA 94158.
11
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.

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.

PMID:
25002752
PMCID:
PMC4113947
DOI:
10.1084/jem.20132477
[Indexed for MEDLINE]
Free PMC Article

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