Abstract
A subset of interleukin (IL)-17A-producing γδ T cells called γδT17 cells may contribute to progression of hypertension. γδT17 cell development is in part dependent upon IL-23 receptor (IL-23R) stimulation. We hypothesized that angiotensin (Ang) II-induced blood pressure (BP) elevation and vascular injury would be blunted in Il23r knock-in (Il23rgfp/gfp) mice deficient in functional IL-23R. To test this hypothesis, we infused wild-type (WT) and Il23rgfp/gfp mice with Ang II (490 ng/kg/min, SC) for 7 or 14 days. We recorded BP by telemetry, assessed vascular function and remodeling using pressurized myography, and profiled T cell populations and cytokine production by flow cytometry. An additional set of Il23rgfp/gfp mice was infused with Ang II for 7 days and injected with interferon (IFN)-γ-neutralizing or control antibodies. Il23rgfp/gfp mice had smaller and stiffer mesenteric arteries and were not protected against Ang II-induced BP elevation. BP was higher in Il23rgfp/gfp mice than WT mice from day 3 until day 9 of Ang II infusion. Il23rgfp/gfp mice had less γδT17 cells and more IFN-γ-producing γδ, CD4+, and CD8+ T cells than WT mice. Seven days of Ang II infusion led to increased IFN-γ-producing γδ, CD4+, and CD8+ T cells in Il23rgfp/gfp mice, whereas only IFN-γ-producing γδ T cells were increased in WT mice. Blocking IFN-γ with a neutralizing antibody reduced the pressor response to 7 days of Ang II infusion in Il23rgfp/gfp mice. Functional IL-23R deficiency was associated with increased IFN-γ-producing T cells and exaggerated initial development of Ang II-induced hypertension, which was in part mediated by IFN-γ.
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Acknowledgements
We are grateful to Veronique Michaud for excellent technical support.
Funding
The work of the authors was supported by the Canadian Institutes of Health Research (CIHR) First Pilot Foundation Grant 143348, a Canada Research Chair (CRC) on Hypertension and Vascular Research by the CRC Government of Canada/CIHR Program, a Distinguished James McGill Professorship Award, and by the Canada Fund for Innovation, to ELS, by the Fonds de recherche Santé Quebec (FRQS) bourse 289184, Lady Davis Institute/TD Bank Studentship award and CIHR Canada Graduate Scholarship to BGS and by the McGill Department of Medicine Gordon Phillips Fellowship to KC.
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Shokoples, B.G., Comeau, K., Higaki, A. et al. Angiotensin II-induced a steeper blood pressure elevation in IL-23 receptor-deficient mice: Role of interferon-γ-producing T cells. Hypertens Res 46, 40–49 (2023). https://doi.org/10.1038/s41440-022-01055-3
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DOI: https://doi.org/10.1038/s41440-022-01055-3
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