Nox2 in regulatory T cells promotes angiotensin II-induced cardiovascular remodeling.
Nox2 in regulatory T cells promotes angiotensin II-induced cardiovascular remodeling.
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调节性T细胞中的NOX2促进了血管紧张素II诱导的心血管重塑。
DOI：
10.1172/jci97490
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发表时间：
2018-07-02
期刊：
影响因子：
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通讯作者：
Shah AM
中科院分区：
文献类型：
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作者：
Emmerson A;Trevelin SC;Mongue-Din H;Becker PD;Ortiz C;Smyth LA;Peng Q;Elgueta R;Sawyer G;Ivetic A;Lechler RI;Lombardi G;Shah AM
产超氧化物的酶Nox2促进由肾素 - 血管紧张素系统激活引发的高血压和心血管重塑。多种表达Nox2的细胞与血管紧张素II诱导（Ang II诱导）的病理生理学有关，但Nox2在白细胞亚群中的重要性知之甚少。在此，我们研究了Nox2在T细胞，特别是调节性T细胞（Tregs）中的作用。全身性Nox2缺陷的小鼠在基线状态下心脏中Tregs数量增加，而Ang II诱导的效应T细胞（Teff）浸润受到抑制。为了研究Treg中Nox2的作用，我们构建了一种CD4靶向Nox2缺陷的小鼠品系（Nox2fl/flCD4Cre+）。这些动物表现出对Ang II诱导的高血压和心脏重塑的抑制，这与组织驻留Tregs增加以及浸润性Teffs（包括Th17细胞）减少有关。通过抗CD25抗体清除Tregs可逆转Nox2fl/flCD4Cre+小鼠的保护作用。从机制上讲，Nox2 -/y Tregs在体外对Teff增殖的抑制作用比野生型（WT）Tregs更强，FoxP3和NF - κB的核水平升高，并且CD25、CD39和CD73的转录增强。Tregs的过继转移证实，Nox2缺陷细胞对Ang II诱导的心脏重塑比野生型细胞具有更强的抑制作用。这些结果确定了Nox2在调节Tregs抑制作用方面先前未被认识的作用，该作用会增强高血压和心脏重塑。
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.