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 are still not well understood. The stress response is associated with peripheral inflammation suggesting that stress hormones including glucocorticoids and catecholamines could 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. Here we investigated the dynamic relationship between stress hormones and neutrophils and their contribution to mood disorders. We found that chronic restraint stress leads to plasma elevation of neutrophil extracellular traps (NETs) and increased NET formation in mice. Interestingly, the stress hormones, cortisol and epinephrine induce NET formation in human neutrophils ex vivo. Activation of neutrophils to form NETs leads to their increased expression of adrenergic and glucocorticoid receptors and neutrophil production of both cortisol and epinephrine indicating an autocrine/paracrine mechanism for the regulation of neutrophil inflammatory response by stress hormones. Strikingly, administration of NET components to mice induces depressive-like behavior. Moreover, activation of the glucocorticoid receptor in human volunteers leads to increase in gene expression of NET proteins. Furthermore, patients with major depressive disorder show gene upregulation of NET proteins. Our data highlights 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.