Research ArticleINFLAMMATION

ATP release drives heightened immune responses associated with hypertension

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Science Immunology  28 Jun 2019:
Vol. 4, Issue 36, eaau6426
DOI: 10.1126/sciimmunol.aau6426

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Hypertension-induced alarm signal fires up T cells

Human hypertension is a highly prevalent disease known to be associated with chronic low-grade inflammation. Zhao et al. used mouse models to look for hypertension-induced proinflammatory molecules that contribute to promoting T cell activation and propagating inflammation. Consistent elevations in plasma levels of the alarmin molecule ATP were identified in hypertensive mice. Increased ATP concentrations promoted T cell responses by enhancing expression of the CD86 costimulatory molecule on antigen-presenting cells, an effect mediated through the P2X7 purinergic receptor. Elevations of plasma ATP were also detected in a cohort of hypertensive human patients compared with normotensive controls. The results of this study identify ATP release and the ATP-P2X7 signaling axis as potential targets to help rein in the proinflammatory sequelae associated with chronic hypertension.

Abstract

The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how elevated blood pressure initiates inflammation is unknown, as are the effects of high blood pressure on innate and adaptive immune responses. We now report that hypertensive mice have increased T cell responses to antigenic challenge and develop more severe T cell–mediated immunopathology. A root cause for this is hypertension-induced erythrocyte adenosine 5′-triphosphate (ATP) release, leading to an increase in plasma ATP levels, which begins soon after the onset of hypertension and stimulates P2X7 receptors on antigen-presenting cells (APCs), increasing APC expression of CD86. Hydrolyzing ATP or blocking the P2X7 receptor eliminated hypertension-induced T cell hyperactivation. In addition, pharmacologic or genetic blockade of P2X7 receptor activity suppressed the progression of hypertension. Consistent with the results in mice, we also found that untreated human hypertensive patients have significantly elevated plasma ATP levels compared with treated hypertensive patients or normotensive controls. Thus, a hypertension-induced increase in extracellular ATP triggers augmented APC and T cell function and contributes to the immune-mediated pathologic changes associated with hypertensive disease.

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