Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling in male mice
Inflammation is increasingly recognized as a risk factor for psychiatric disorders. Animal models of stress and stress-related disorders are associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We characterized the immune response to chronic social defeat (CSD) stress at brain border regions in male mice. Here we show that chronic, but not acute, stress causes neutrophil accumulation in the meninges-i.e., "meningeal neutrophilia"- but not the brain. CSD promotes neutrophil trafficking to meninges via vascular channels originating from skull bone marrow (BM). Transcriptional analysis suggests CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protects against the negative behavioral effects of CSD stress. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitlate development of new therapies for stress-related disorders.
Authors
- Virginia H. Sun (ORCID: https://orcid.org/0000-0003-1387-2994)
- Joshua D. Samuels (ORCID: https://orcid.org/0000-0001-5662-3758)
- Allison E. DePuyt
- Michael L. Lehmann (ORCID: https://orcid.org/0000-0003-4476-8268)
- Edward Thomas Bullmore (ORCID: https://orcid.org/0000-0002-8955-8283)
- Ferenc Livák (ORCID: https://orcid.org/0000-0003-2833-585X)
- Stacey L. Kigar (ORCID: https://orcid.org/0000-0003-2636-0648)
- Miles Herkenham (ORCID: https://orcid.org/0000-0003-2228-4238)
- Menna Ruth Clatworthy (ORCID: https://orcid.org/0000-0002-3340-9828)
- Chelsie N. Poffenberger (ORCID: https://orcid.org/0000-0001-9643-3457)
- Mary-Ellen Lynall (ORCID: https://orcid.org/0000-0002-1939-7525)
- Nicole E. Eassa (ORCID: https://orcid.org/0000-0002-9607-1721)
- Abdel G. Elkahloun (ORCID: https://orcid.org/0000-0001-7085-0762)
- Robert Atkinson
- Samuel J. Listwak
Institutions
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- National Human Genome Research Institute (US)
- National Cancer Institute (US)
- National Institute of Mental Health (US)
- National Institute of Mental Health (CZ)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41467-025-62840-5
- Citations
- 3
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.53
Funders
- U.S. Department of Health and Human Services
- UK Research and Innovation
- National Institute for Health and Care Research
- Department of Health and Social Care
- National Institutes of Health
- Medical Research Council
- Programme Grants for Applied Research
- NIHR Cambridge Biomedical Research Centre
- National Institute of Mental Health
- National Cancer Institute