Interleukin-21 and endothelial dysfunction in hypertension

项目摘要 在美国，高血压是最常见的主要诊断，即使接受治疗的个体也仍然存在 心血管风险升高，表明目前的治疗方案是次优的。新出现的证据 提示免疫系统的激活是高血压的一个中心特征，特别是CD 4 + T辅助细胞。 淋巴细胞和T细胞衍生的细胞因子。高血压的特征是T淋巴细胞浸润到 终末器官如脉管系统、肾脏和心脏。白细胞介素-21（IL-21）是一种促炎细胞因子 由多个辅助性T细胞亚群产生，增强辅助性T细胞产生IL-17 A。一个最近 所描述的T外周辅助细胞（TPH）细胞的CD 4+亚群显示在以下情况下产生IL-21： 自身免疫性疾病IL-17 A是一种已知有助于高血压免疫激活的细胞因子， 直接在内皮上。初步研究表明，IL-21缺陷小鼠具有钝化的 高血压反应和IL-21的中和都逆转了内皮功能障碍并降低了血液流变学。 老鼠的压力这一令人信服的证据表明，IL-21是一个关键的细胞因子驱动激活的细胞因子。 高血压中的适应性免疫系统和终末器官损伤;然而，哪些T细胞亚群产生IL-21 IL-21是否直接作用于内皮尚不清楚。该项目将（a）测试 假设TPH细胞是高血压中IL-21的主要来源，并且产生IL-21的T细胞是 足以在体内促进高血压，（B）机械地确定IL-21在内皮细胞中的作用， 功能障碍和（c）评估尼古丁中和治疗对临床心血管疾病的长期影响 结果。这些研究的完成将对免疫系统的潜在机制产生重要的见解。 激活高血压，并确定潜在的新的细胞靶点。

PROJECT SUMMARY Hypertension is the most common primary diagnosis in the United States, and even treated individuals remain at elevated cardiovascular risk, suggesting that current therapeutic options are suboptimal. Emerging evidence implicates activation of the immune system as a central feature of hypertension, particularly CD4+ T helper lymphocytes and T cell-derived cytokines. Hypertension is characterized by infiltration of T lymphocytes into end-organs such as the vasculature, kidney, and heart. Interleukin-21 (IL-21) is a pro-inflammatory cytokine produced by multiple T helper subsets that potentiates IL-17A production by T helper cells. A recently described CD4+ subset of T peripheral helper cells (TPH) cells were shown to produce IL-21 in the context of autoimmune disease. IL-17A is a cytokine known to contribute to immune activation in hypertension and act directly on the endothelium. Preliminary studies have shown that IL-21 deficient mice have a blunted hypertensive response, and neutralization of IL-21 both reverses endothelial dysfunction and lowers blood pressure in mice. This compelling evidence suggest that IL-21 is a key cytokine driving activation of the adaptive immune system and end-organ damage in hypertension; however, which T cell subsets produce IL-21 in hypertension and whether IL-21 acts directly on the endothelium is unknown. This project will (a) test the hypothesis that TPH cells are the primary source of IL-21 in hypertension and that IL-21 producing T cells are sufficient to promote hypertension in vivo, (b) mechanistically determine the role of IL-21 in endothelial dysfunction and (c) evaluate the long-term impact of cytokine-neutralizing therapy on clinical cardiovascular outcomes. The completion of these studies will yield critical insights into the mechanism underlying immune activation in hypertension and identify potential novel cellular targets.