Chronic exposure to stress predisposes to higher autoimmune susceptibility in C57BL/6 mice: Glucocorticoids as a double-edged sword

Authors

  • Idan Harpaz,

    1. Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
    2. The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
    3. The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
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  • Shai Abutbul,

    1. The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
    2. The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
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  • Anna Nemirovsky,

    1. The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
    2. The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
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  • Ram Gal,

    1. Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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  • Hagit Cohen,

    1. Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
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  • Alon Monsonego

    Corresponding author
    1. The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel
    • The Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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Errata

This article is corrected by:

  1. Errata: Correction Volume 43, Issue 11, 3076, Article first published online: 20 November 2013

Full correspondence: Prof. Alon Monsonego, Ben-Gurion University of the Negev, Beer Sheva, 84308, Israel

Fax: +972-8-6479051

e-mail: alonmon@bgu.ac.il

Abstract

Stress activates the hypothalamic-pituitary-adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4+CD25+ Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.

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