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Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety

Molecular Psychiatry volume 23, pages 1421–1431 (2018)Cite this article

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Abstract

Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+ neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1KO specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.

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Acknowledgements

This study was supported by National Institute of Health (NIMH) grants R01-MH-093473 and R01-MH093472 to JFS. DBM, MDW, CMS and BLJ were supported by NIDCR Training Grant T32-DE014320. DBM was supported by F31-MH-109234. Authors thank Brian West at Plexxikon for the use of PLX5622. We thank The Ohio State University Comprehensive Cancer Center's (OSUCCC) Analytical Cytometry and Nucleic Acid Shared Resources.

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Author notes

  1. K Ramirez-Chan

    Present address: 5Current address: College of Dentistry and Neuroscience Research Center, University of Costa Rica, San José, Costa Rica.,

  2. D B McKim and M D Weber: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    D B McKim, M D Weber, A Niraula, B L Jarrett & J P Godbout

  2. Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA

    D B McKim, M D Weber, A Niraula, C M Sawicki, X Liu, B L Jarrett, K Ramirez-Chan, Y Wang, R M Roeth, A D Sucaldito, C G Sobol, N Quan & J F Sheridan

  3. Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA

    N Quan, J F Sheridan & J P Godbout

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Correspondence to J F Sheridan or J P Godbout.

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McKim, D., Weber, M., Niraula, A. et al. Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry 23, 1421–1431 (2018). https://doi.org/10.1038/mp.2017.64

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