Interleukin-10 Released by CD4 ⁺ CD25 ⁺ Natural Regulatory T Cells Improves Microvascular Endothelial Function Through Inhibition of NADPH Oxidase Activity in Hypertensive Mice

Abstract

Objective We previously demonstrated that a reduced number of CD4+CD25+-regulatory T cells (Tregs) was associated with microvascular dysfunction in hypertension. However, the underlying mechanism by which Tregs regulate vascular endothelial function remains unknown. Methods and Results Control and interleukin (IL)-10–/– knockout mice were infused with angiotensin II (400 ng/kg/min) for 2 weeks (hypertensive [HT] and HT-IL-10–/–). Endothelium-dependent relaxation (EDR) in response to acetylcholine was significantly reduced in mesenteric resistance artery (MRA) from HT and HT-IL-10–/– compared with control and IL-10–/– mice. Importantly, the incubation of MRA from HT mice with the conditioned media of cultured Tregs, isolated from control mice, reduced NADPH oxidase activity and improved EDR, whereas no effect was observed in MRA from control mice incubated with the same media. These effects were reversed when MRAs were preincubated with IL-10 antibody or IL-10 receptor antagonist, whereas incubation with transforming growth factor-β receptor antagonist had no effect. The transfer of cultured Tregs, isolated from control mice, into HT-IL-10–/– mice reduced systolic blood pressure (SBP) and NADPH oxidase activity and improved EDR in MRA compared with untreated HT-IL-10–/– mice. In vivo treatment of HT mice with IL-10 (1000 ng/mouse) significantly reduced SBP and NADPH oxidase activity and improved EDR in MRA compared with untreated HT mice. The transfer of cultured Tregs, isolated from IL-10–/– mice, into HT mice did not reduce SBP or NADPH oxidase activity or improve EDR. The incubation of MRA from HT mice with apocynin improved EDR, whereas NADPH oxidase substrate attenuated EDR in MRA from control mice, which was reversed with exogenous IL-10. Conclusion These data demonstrate that IL-10 released from Tregs attenuates NADPH oxidase activity, which is a critical process in the improvement of microvascular endothelial function in hypertension, suggesting that Tregs/IL-10 could be a therapeutic target for treatment of vasculopathy in hypertension.

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“…In contrast, M2 macrophages secrete IL-10, which can improve the insulin signaling impaired by proinflammatory cytokines (5,18). IL-10 also suppresses NADPH-mediated oxidative stress in the vasculature (32). Studies employing deletion of MR from specific cell types in mice suggest macrophage MRs play a key role in modulating macrophage polarization and promoting cardiac hypertrophy, inflammation, and fibrosis (10,11,51,79).…”

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