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Neutrophil-Mediated Effects at the Blood Brain Barrier Following Chronic Stress

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  • UserDr Stacey Kigar (Department of Medicine and Psychiatry, University of Cambridge)
  • ClockSunday 14 March 2021, 11:30-12:20
  • HouseOnline.

If you have a question about this talk, please contact Miroslava Novoveska.

Annual TCSS Symposium 2021

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Chronic stress is a major risk factor for major depressive disorder (MDD) and is associated with altered white blood cell (WBC) counts and increased cytokine production. However, the relationship between peripheral immune changes and altered mood is unclear, as access to the CNS by peripheral WBCs and cytokines is tightly regulated by the blood brain barrier (BBB). Under conditions of homeostasis, WBCs do not appreciably enter the parenchyma, instead residing in spaces just inside the BBB such as the leptomeninges, from which they surveil the CNS for pathogens or damage. Importantly, cytokines released by WBCs from within this space may modulate behavior and neuronal activity, as has recently been shown for type II interferons and IL-17. We set out to characterize the dynamic profile of circulating and meningeal WBCs in mice undergoing chronic social defeat (CSD) stress, a well-characterized mouse model for depressive-like behavior. We found that a single social defeat encounter is sufficient to induce more than a 4x increase in the number of blood neutrophils, consistent with reports that blood neutrophil levels rapidly increase following acute exposure to stress via sympathetic innervation of bone marrow reservoirs. Conversely, acute stress had no effect on neutrophil prevalence in the leptomeningeal compartment; instead, it took completion of the 14d CSD paradigm to see an approximate 1.5x increase in meningeal neutrophils. Drop-seq analysis of control vs. CSD meninges independently confirmed that stressed animals have more (~2x) neutrophils, shown further by both high-dimensional flow cytometry and immunohistochemical analysis. Our evidence suggests neutrophil chemotaxis to the BBB can be blocked via administration of chemokine receptor-targeting antibodies, which may in turn improve behavioral outcomes for chronically stressed mice. Given both that pharmacological interventions targeting serotonergic pathways are ineffective for a large swath of MDD patients – particularly those with increased peripheral inflammation—and recent reports that circulating neutrophil levels correlate strongly with MDD symptom severity, this data has exciting implications as a potential biomarker and future therapeutic target for treatment of depression.

This talk is part of the Trinity College Science Society (TCSS) series.

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