ATP release mediates the over‐activation of adaptive immune response associated with hypertension

Abstract

The cause of most hypertensive disease is unclear, but inflammation appears critical in disease progression. However, how an elevated blood pressure (BP) initiates inflammation is unknown and the effects of high BP on immune responses are unfathomed. To study this, we immunized angiotensin II (Ang II) induced hypertensive mice and normotensive mice with ovalbumin (OVA) and adjuvants for 7 days. 2‐fold more OVA‐specific CD8+ T cells were present in the blood (2.7 ± 0.23% vs. 1.2 ± 0.47%, P<0.05) and the spleen (2.62 ± 0.31% vs. 1.31 ± 0.17%, P<0.05) of hypertensive mice as compared to normotensive animals. Two models of autoimmune disease were studied to determine if the exaggerated T cell responses in hypertension translate into increased tissue pathology. RIP‐mOVA is a transgenic mouse line that expresses OVA in pancreatic islet β cells. These mice were made hypertensive with either Ang II or L‐NAME. When OVA‐specific OT‐I T cells were infused into RIP‐mOVA mice, the hypertensive mice had significantly more OT‐I T cells infiltration into the pancreas (AngII 75%, L‐NAME 73%, control 13%) and developed severer diabetes (Blood glucose: AngII 331, L‐NAME 315, control 168 mg/dl). Concanavalin A induced hepatitis was also significantly worsened by hypertension as compared to the pathology observed in normotensive mice. A critical difference in hypertensive mice was the upregulation of CD86 on antigen presenting cells (APCs) (MFI:1928 ± 24.01 vs.1798 ± 20.96, P<0.05). Plasma ATP levels rose as early as 3 days after the induction of hypertension and reach a peak level of 3 μM after 2 weeks of hypertension, which exactly parallel the kinetics of CD86 expression on APCs. Hydrolyzing ATP or blocking the P2X7 receptor normalized CD86 expression and eliminated hypertension‐induced T cell over‐activation. Further, blind analysis shows untreated hypertensive patients have substantially elevated plasma ATP levels (2.21 ± 0.99 μM, n = 27) compared to treated hypertensive patients (0.94 ± 0.34 μM, n = 17) or normotensive controls (0.63 ± 0.38 μM, n =30). A linear trend was observed between ATP levels and systolic BP and diastolic BP among all subjects. These studies indicate ATP and CD86 as loci to potentially control hypertension associated inflammation.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.