补体 C3a 和 C5a 受体缺乏通过调节性 T 细胞预防血管紧张素 II 诱导的高血压。
Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II-Induced Hypertension via Regulatory T Cells.
机构信息
From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China (X.-H.C., C.-C.R., Q.G., Y.M., J.-Z.X., D.-R.C., D.-L.Z., P.-J.G.); and Laboratory of Vascular Biology (X.-H.C., C.-C.R., Z.-B.Z., J.-R.L., P.-J.G.) and Key Laboratory of Stem Cell Biology (X.-H.C., C.-C.R., Z.-B.Z., J.-R.L., P.-J.G.), Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
出版信息
Circ Res. 2018 Mar 30;122(7):970-983. doi: 10.1161/CIRCRESAHA.117.312153. Epub 2018 Feb 5.
RATIONALE
Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear.
OBJECTIVE
We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs).
METHODS AND RESULTS
We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR-/-), or C5aR-deficient (C5aR-/-) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals.
CONCLUSIONS
C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.
背景
炎症和免疫在高血压的发生发展中起着关键作用。补体激活介导的固有免疫反应参与了高血压和靶器官损伤的调节。然而，补体介导体液免疫反应是否能调节高血压患者的血压升高尚不清楚。
目的
我们旨在确定 C3aR（补体成分 3a 受体）和 C5aR（补体成分 5a 受体）是否可以通过调节调节性 T 细胞（Tregs）来调节血压。
方法和结果
我们发现血管紧张素 II（Ang II）诱导的高血压导致 Foxp3（叉头框 P3）+Tregs 中 C3aR 和 C5aR 的表达升高。通过使用 C3aR 和 C5aR DKO（双敲除）小鼠，我们发现与 WT（野生型）、单个 C3aR 缺陷（C3aR-/-）或 C5aR 缺陷（C5aR-/-）小鼠相比，C3aR 和 C5aR 缺陷共同显著降低了 Ang II 引起的收缩压和舒张压。流式细胞术分析显示，DKO 小鼠也阻止了 Ang II 诱导的肾脏和血液中 Treg 的减少。组织学分析表明，与 WT 小鼠相比，DKO 小鼠在 Ang II 治疗后肾脏和血管结构重塑和损伤减轻。体外，Ang II 能够刺激培养的 CD4+CD25+天然 Tregs 中 C3aR 和 C5aR 的表达。CD3 和 CD28 抗体刺激下调 WT 但不 DKO Tregs 中的 Foxp3 表达。更重要的是，用 CD25 抗体耗尽 Tregs 消除了 DKO 小鼠对 Ang II 诱导的高血压和靶器官损伤的保护作用。与 WT Treg 转移相比，DKO Treg 的过继转移显示出对 Ang II 诱导的高血压更强的保护作用。此外，我们发现高血压患者中 Foxp3+Tregs 中的 C5aR 表达高于血压正常的个体。
结论
C3aR 和 C5aR DKO 介导的 Treg 功能可预防 Ang II 诱导的高血压和靶器官损伤。针对 Tregs 中的 C3aR 和 C5aR 可能是一种治疗高血压的新方法。
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