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A gut feeling to stress enhances neutrophil-mediated vascular occlusion

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Science Translational Medicine  12 Aug 2020:
Vol. 12, Issue 556, eabd4776
DOI: 10.1126/scitranslmed.abd4776

Abstract

Psychological stress alters TH17 cell response to gut microbiome and triggers acute vascular-occlusion induced by aged-neutrophils in sickle cell disease.

Psychological stress has long been associated with negative cardiovascular outcomes. Potential mechanisms include the activation of the sympathetic nervous system (SNS) and/or the hypothalamic-pituitary-adrenal (HPA) axis and increased inflammation. However, how psychological stress influences specific immune responses and cardiovascular disease (CVD) state remains elusive. Sickle cell disease (SCD) is a genetic condition caused by a mutation of the ß-globin gene that causes morphological deformation of red blood cells (RBC) to a sickle shape. Patients with SCD are sensitive to stress and experience acute vaso-occlusive episodes (VOE) with an inflammatory component that can result in vital organ damage. Importantly, the mechanistic link between psychological stress, inflammation, and VOE remains to be understood.

Xu et. al. used a SCD mouse model and observed the existence of specific brain-vascular stress signals in CVD. The authors experimentally showed that psychological stress enhanced the severity of VOE and reduced survival of SCD mice. VOE exacerbation was mediated by aged neutrophil expansion, which was dependent on an intact commensal gut microbiota and the activation of the interleukin-17 (IL-17)/granulocyte colony-stimulating factor (G-CSF) signaling. Specifically, glucocorticoid expression in response to HPA axis activation induced gut permeability and consequent segmented filamentous bacteria (SFB) antigen presentation to TH17 cells in the lamina propria to activate the IL-17/G-CSF pathway. The clinical translation of this pathway is limited to the fact that SFB are only detectable in rodents and a similar role for TH17-activating microbiota in humans remains to be established.

The identification of a brain-gut axis modulating immune responses and vascular function in response to psychological stress might be relevant for other cardiovascular conditions aggravated by stress. Specific to SCD, this study offers opportunities to explore the clinical relevance of the identified pathway and possibly identify potential treatments for improving life quality and clinical outcome in patients.

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