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Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety

  • Anzela Niraula
    Affiliations
    Division of Biosciences, The Ohio State University, Columbus, Ohio

    Department of Neuroscience, The Ohio State University, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio
    Search for articles by this author
  • Kristina G. Witcher
    Affiliations
    Division of Biosciences, The Ohio State University, Columbus, Ohio

    Department of Neuroscience, The Ohio State University, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio
    Search for articles by this author
  • John F. Sheridan
    Correspondence
    Address correspondence to Jonathan P. Godbout, Ph.D., or John F. Sheridan, Ph.D. M.S., Department of Neuroscience, 231 IBMR Building, 460 Medical Center Drive, Columbus, OH.
    Affiliations
    Division of Biosciences, The Ohio State University, Columbus, Ohio

    Department of Neuroscience, The Ohio State University, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio

    Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio
    Search for articles by this author
  • Jonathan P. Godbout
    Correspondence
    Address correspondence to Jonathan P. Godbout, Ph.D., or John F. Sheridan, Ph.D. M.S., Department of Neuroscience, 231 IBMR Building, 460 Medical Center Drive, Columbus, OH.
    Affiliations
    Division of Biosciences, The Ohio State University, Columbus, Ohio

    Department of Neuroscience, The Ohio State University, Columbus, Ohio

    Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio

    Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, Ohio
    Search for articles by this author

      Abstract

      Background

      Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress.

      Methods

      Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later.

      Results

      Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell–sorted blood monocytes (CD11b+/Ly6Chi) and brain monocytes (CD11b+/CD45hi) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL-6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1β, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL-6.

      Conclusions

      Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety.

      Keywords

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