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Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4–Stat5–NF-κB pathway

医学 盐皮质激素受体 树突状细胞 染色质免疫沉淀 基因敲除 流式细胞术 内分泌学 过继性细胞移植 癌症研究 血管紧张素II 内科学 免疫学 T细胞 受体 细胞培养 生物 免疫系统 遗传学 基因 生物化学 基因表达 发起人
作者
Wei Wang,Hong Zhu,Yi-Tong Pan,Da Shang,Lin‐Juan Du,Lan Bai,Shiwei Zhu,Wen-Zhen Lin,Xingyu Zhang,Haixia Lü,Chao Bi,Yuan Liu,Yan Liu,Hui Xiao,Youcun Qian,Bin Zhou,Ruogu Li,Sheng‐Zhong Duan
出处
期刊:European Heart Journal [Oxford University Press]
标识
DOI:10.1093/eurheartj/ehae670
摘要

Abstract Background and Aims Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. Methods Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. Results Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. Conclusions Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4–Stat5–NF-κB signalling, and blockade of DC MR is beneficial for treating hypertension.
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