Caught in the NET: Stress-Driven Neutrophil Dynamics Alter Behavior 2258480

Abstract Introduction Despite recognized neuroendocrine-immune crosstalk, the effects of psychological stress on neutrophil extracellular trap formation (NETosis) and associated behavioral outcomes are poorly understood. Methods In this study, we investigated the effect of stress and stress hormones on NETosis using a chronic stress paradigm in C57BL/6J mice in vivo and by activating primary human neutrophils in vitro with stress hormones. Results C57BL/6J mice exposed to chronic stress (21days), showed extensive neutrophil expansion and increased NET formation in plasma and isolated neutrophils, quantified using SYTOX-based fluorescence and microscopic assays. Furthermore, activation of human neutrophils with stress hormones epinephrine and cortisol resulted in robust NET formation characterized by neutrophil elastase and visualized by confocal microscopy. Interestingly, induction of NETS in human neutrophils using phorbol myristate acetate (PMA) also increased β2-adrenergic and glucocorticoid receptor expression determined by flow cytometry. Following this, injection of NET components to mice caused behavioral changes such as reduced locomotor activity in open field test. Conclusion Together, our results indicate that stress hormones directly promote NETosis and that neutrophil-neuroendocrine signaling contribute to further stress associated behavioral changes. These findings identify a direct mechanism linking chronic stress, innate immunity and behavioral changes and highlight new targets in psychiatric disease pathophysiology. Funding Source Northeastern university Topic Categories Neuroimmunology (NEUR)