Abstract
Microglia are the main innate immune cells in the central nervous system that are actively involved in maintaining brain homeostasis and diseases. T cell Ig and mucin domain protein 3 (Tim-3) plays critical roles in both the adaptive and the innate immune system and is an emerging therapeutic target for treatment of various disorders. In the brain Tim-3 is specifically expressed on microglia but its functional role is unclear. Here, we showed that Tim-3 was up-regulated on microglia by ATP or LPS stimulation. Tim-3 activation with antibodies increased microglia expression of TGF-β, TNF-α and IL-1β. Blocking of Tim-3 with antibodies decreased the microglial phagocytosis of apoptotic neurons. Tim-3 blocking alleviated the detrimental effect of microglia on neurons and promoted NG2 cell differentiation in co-cultures. Finally, MAPKs namely ERK1/2 and JNK proteins were phosphorylated upon Tim-3 activation in microglia. Data indicated that Tim-3 modulates microglia activity and regulates the interaction of microglia-neural cells.
Keywords:
MAPK; Microglia; NF-κB; NG2 cell; Neuron; Tim-3.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / pharmacology
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Animals
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Animals, Newborn
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Antibodies / pharmacology
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Apoptosis / drug effects
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Brain / cytology
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Brain / drug effects
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Brain / immunology*
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Coculture Techniques
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Gene Expression Regulation
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Hepatitis A Virus Cellular Receptor 2
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Immunity, Innate
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / immunology
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / immunology
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Mice
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Mice, Inbred BALB C
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Microglia / cytology
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Microglia / drug effects
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Microglia / immunology*
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / immunology
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / immunology
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Neurons / cytology
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Neurons / drug effects
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Neurons / immunology*
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Phagocytosis / drug effects
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Phosphorylation / drug effects
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Primary Cell Culture
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Receptors, Virus / agonists
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Receptors, Virus / genetics
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Receptors, Virus / immunology*
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / immunology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Antibodies
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Havcr2 protein, mouse
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Hepatitis A Virus Cellular Receptor 2
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Interleukin-1beta
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Lipopolysaccharides
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Receptors, Virus
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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Adenosine Triphosphate
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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MAP Kinase Kinase 4