Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling
Amber Emmerson, … , Giovanna Lombardi, Ajay M. Shah
Amber Emmerson, … , Giovanna Lombardi, Ajay M. Shah
Published April 24, 2018
Citation Information: J Clin Invest. 2018;128(7):3088-3101. https://doi.org/10.1172/JCI97490.
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Research Article Cardiology Immunology

Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling

Abstract

The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II–induced (Ang II–induced) pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline, whereas Ang II–induced effector T cell (Teff) infiltration was inhibited. To investigate the role of Treg Nox2, we generated a mouse line with CD4-targeted Nox2 deficiency (Nox2fl/flCD4Cre+). These animals showed inhibition of Ang II–induced hypertension and cardiac remodeling related to increased tissue-resident Tregs and reduction in infiltrating Teffs, including Th17 cells. The protection in Nox2fl/flCD4Cre+ mice was reversed by anti-CD25 antibody depletion of Tregs. Mechanistically, Nox2–/y Tregs showed higher in vitro suppression of Teff proliferation than WT Tregs, increased nuclear levels of FoxP3 and NF-κB, and enhanced transcription of CD25, CD39, and CD73. Adoptive transfer of Tregs confirmed that Nox2-deficient cells had greater inhibitory effects on Ang II–induced heart remodeling than WT cells. These results identify a previously unrecognized role of Nox2 in modulating suppression of Tregs, which acts to enhance hypertension and cardiac remodeling.

Authors

Amber Emmerson, Silvia Cellone Trevelin, Heloise Mongue-Din, Pablo D. Becker, Carla Ortiz, Lesley A. Smyth, Qi Peng, Raul Elgueta, Greta Sawyer, Aleksandar Ivetic, Robert I. Lechler, Giovanna Lombardi, Ajay M. Shah

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Figure 9

Schematic of cellular and molecular mechanisms through which Nox2 in CD4+ T cells regulates Ang II–induced hypertension and heart remodeling.

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Schematic of cellular and molecular mechanisms through which Nox2 in CD4...
Deficiency of Nox2 in Tregs results in increased numbers of Tregs in the heart and vessels and protects against the development of hypertension, interstitial cardiac fibrosis, and cardiomyocyte hypertrophy. Mechanistically, the deficiency of Nox2 in Tregs enhances their suppressive function through an increase in nuclear levels of FoxP3 and NF-κB activation, and higher levels of GITR, CTLA-4, CD39, CD73, and CD25. The higher CD25 levels may drive an increased STAT5 phosphorylation under IL-2 stimulation, and lead to a positive feedback promoting suppression. The deficiency of Nox2 also drives a change in balance between Tregs and Th17 cells to a more antiinflammatory profile, with higher IL-10 and lower IL-17 levels.