Dynamic interaction between stress hormones and neutrophils promotes neutrophil extracellular trap formation with behavioral consequences.

Recent studies have highlighted the crosstalk between neuroendocrine responses and the immune system, but the mechanisms underlying this cooperation remain poorly understood. The stress response is associated with peripheral inflammation suggesting that stress hormones including glucocorticoids and catecholamines modulate the function of innate immune cells like neutrophils. Likewise, inflammatory mediators produced by immune cells are known to contribute to psychiatric diseases like major depressive disorder (MDD). Here we investigated the dynamic relationship between stress hormones and neutrophils and their contribution to mood disorders. We found that chronic restraint stress led to a progressive elevation of plasma corticosterone (∼31.6% at day 14 and ∼46.1% at day 21) and increased neutrophil extracellular traps (NETs), evidenced by ∼60% higher extracellular DNA. Interestingly, the stress hormones, cortisol and epinephrine induced NET formation in human neutrophils ex vivo, with cortisol producing a strong dose-dependent increase (∼5-6-fold). Notably, NET-forming neutrophils upregulated adrenergic and glucocorticoid receptors and produced both cortisol and epinephrine, indicating a feed-forward autocrine/paracrine mechanism. Strikingly, administration of NET components to mice induced depressive-like behavior, resulting in ∼24% reduction in locomotor activity and exploratory behavior. Furthermore, glucocorticoid receptor activation in human volunteers increased gene expression of NET-associated proteins, and patients with MDD showed upregulation of these same genes. Our data highlight the bi-directional relationship between neuroendocrine processes and neutrophils that contribute to stress-induced increase in inflammation and the role of neutrophil inflammatory responses in propagation of behavioral changes following stress.