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

Article


Emmerson, Amber, Trevelin, Silvia Cellone, Mongue-Din, Heloise, Becker, Pablo D., Ortiz, Carla, Smyth, L., Peng, Qi, Elgueta, Raul, Sawyer, Greta, Ivetic, Aleksandar, Lechler, Robert I., Lombardi, Giovanna and Shah, Ajay M. 2018. Nox2 in regulatory T cells promotes angiotensin II–induced cardiovascular remodeling. Journal of Clinical Investigation. 128 (7), pp. 3088-3101.
AuthorsEmmerson, Amber, Trevelin, Silvia Cellone, Mongue-Din, Heloise, Becker, Pablo D., Ortiz, Carla, Smyth, L., Peng, Qi, Elgueta, Raul, Sawyer, Greta, Ivetic, Aleksandar, Lechler, Robert I., Lombardi, Giovanna and Shah, Ajay M.
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 (AngII)-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 AngII-induced T-effector cell (Teffs) 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 AngII-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 Ab-depletion of Tregs. Mechanistically, Nox2-/y Tregs showed higher in vitro suppression of Teffs 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 AngII-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.

JournalJournal of Clinical Investigation
Journal citation128 (7), pp. 3088-3101
ISSN1558-8238
Year2018
PublisherAmerican Society for Clinical Investigation
Publisher's version
License
Digital Object Identifier (DOI)doi:10.1172/JCI97490
Web address (URL)https://doi.org/10.1172/JCI97490
Publication dates
Online24 Apr 2018
Print02 Jul 2018
Publication process dates
Deposited30 Apr 2018
Accepted17 Apr 2018
Accepted17 Apr 2018
Copyright information© 2018 Emmerson et al.
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