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Role of Monocyte-Derived MicroRNA106b∼25 in Resilience to Social Stress

  • Madeline L. Pfau
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Caroline Menard
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Psychiatry and Neuroscience, Faculty of Medicine and Cervo Brain Research Center, Université Laval, Quebec City, Quebec, Canada
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  • Flurin Cathomas
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Fiona Desland
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Oncological Science, Tisch Cancer Institute and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Veronika Kana
    Affiliations
    Department of Oncological Science, Tisch Cancer Institute and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Kenny L. Chan
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Yusuke Shimo
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Katherine LeClair
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Meghan E. Flanigan
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Hossein Aleyasin
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Deena M. Walker
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Sylvain Bouchard
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Matthias Mack
    Affiliations
    Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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  • Georgia E. Hodes
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, Virginia
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  • Miriam M. Merad
    Affiliations
    Department of Oncological Science, Tisch Cancer Institute and Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Scott J. Russo
    Correspondence
    Address correspondence to Scott J. Russo, Ph.D., Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, Center for Affective Neuroscience and Friedman Brain Institute, 1425 Madison Avenue, New York, NY 10029.
    Affiliations
    Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York

    Center for Affective Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
    Search for articles by this author

      Abstract

      Background

      Clinical studies suggest that heightened peripheral inflammation contributes to the pathogenesis of stress-related disorders, including major depressive disorder. However, the molecular mechanisms within peripheral immune cells that mediate enhanced stress vulnerability are not well known. Because microRNAs (miRs) are important regulators of immune response, we sought to examine their role in mediating inflammatory and behavioral responses to repeated social defeat stress (RSDS), a mouse model of stress vulnerability that produces susceptible and resilient phenotypes.

      Methods

      We isolated Ly6chigh monocytes via fluorescence-activated cell sorting in the blood of susceptible and resilient mice following RSDS and profiled miR expression via quantitative real-time polymerase chain reaction. Bone marrow chimeric mice were generated to confirm a causal role of the miR-106b∼25 cluster in bone marrow–derived leukocytes in mediating stress resilience versus susceptibility.

      Results

      We found that RSDS produces an increase in circulating Ly6chigh inflammatory monocytes in both susceptible and resilient mice. We next investigated whether intrinsic leukocyte posttranscriptional mechanisms contribute to individual differences in stress response and the resilient phenotype. Of the miRs profiled in our panel, eight were significantly regulated by RSDS within Ly6chigh monocytes, including miR-25-3p, a member of the miR-106b∼25 cluster. Selective knockout of the miR-106b∼25 cluster in peripheral leukocytes promoted behavioral resilience to RSDS.

      Conclusions

      Our results identify the miR-106b∼25 cluster as a key regulator of stress-induced inflammation and depression that may represent a novel therapeutic target for drug development.

      Keywords

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