
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.30.610447
preprint
1
Article
Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling
Kigar Stacey L. http://orcid.org/0000-0003-2636-0648

Lynall Mary-Ellen http://orcid.org/0000-0002-1939-7525

DePuyt Allison E.
Atkinson Robert
Sun Virginia H.
Samuels Joshua D. http://orcid.org/0000-0001-5662-3758

Eassa Nicole E. http://orcid.org/0000-0002-9607-1721

Poffenberger Chelsie N. http://orcid.org/0000-0001-9643-3457

Lehmann Michael L.
Listwak Samuel J.
Livak Ferenc
Elkahloun Abdel G.
Clatworthy Menna R. http://orcid.org/0000-0002-3340-9828

Bullmore Edward T. http://orcid.org/0000-0002-8955-8283

Herkenham Miles http://orcid.org/0000-0003-2228-4238

31 8 2024
2024.08.30.610447https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.30.610447
nihpp-2024.08.30.610447.pdf
Abstract

Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice. We find that chronic, but not acute, stress causes meningeal neutrophil accumulation, and CSD increases neutrophil trafficking in vascular channels emanating from skull bone marrow (BM). Transcriptional analysis suggested CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protected against the anhedonic and anxiogenic effects of CSD stress, potentially through reduced infiltration of IFNAR + neutrophils into the meninges from skull BM. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitate development of new therapies for stress-related disorders.

One sentence summary

Type I interferon sensing neutrophils accumulate in meninges of psychosocially stressed mice via skull bone marrow channels and are associated with the negative behavioral sequelae of stress; blockade of this pathway inhibits neutrophil trafficking and improves behavioral outcomes.
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