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

被引：55

作者：

Emmerson, Amber ^{[1
]}

Trevelin, Silvia Cellone ^{[1
]}

Mongue-Din, Heloise ^{[1
]}

Becker, Pablo D. ^{[2
]}

Ortiz, Carla ^{[2
]}

Smyth, Lesley A. ^{[2
]}

Peng, Qi ^{[2
]}

Elgueta, Raul ^{[2
]}

Sawyer, Greta ^{[1
]}

Ivetic, Aleksandar ^{[1
]}

Lechler, Robert I. ^{[2
]}

Lombardi, Giovanna ^{[2
]}

Shah, Ajay M. ^{[1
]}

机构：

[1] Kings Coll London, British Heart Fdn Ctr, Sch Cardiovasc Med & Sci, London, England

[2] Kings Coll London, Med Res Council, Ctr Transplantat, Sch Immunol & Microbial Sci, London, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2018年 / 128卷 / 07期

关键词：

NF-KAPPA-B; INTERSTITIAL CARDIAC FIBROSIS; NADPH OXIDASE; TRANSCRIPTION-FACTOR; VASCULAR DYSFUNCTION; INDUCED HYPERTENSION; LUNG INFLAMMATION; OXIDATIVE STRESS; HEART-FAILURE; MICE;

D O I：

10.1172/JCI97490

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 (Nox2(fl/fl)CD4Cre(+)). 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 Nox2(fl/fl)CD4Cre(+) 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-kappa B, 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.

引用

页码：3088 / 3101

页数：14

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