Interleukin-21 and endothelial dysfunction in hypertension

项目总结 高血压是美国最常见的主要诊断，即使是接受治疗的人也仍然 心血管风险增加，这表明目前的治疗方案不是最优的。新出现的证据 提示免疫系统的激活是高血压的一个主要特征，尤其是CD4+T辅助细胞 淋巴细胞和T细胞衍生的细胞因子。高血压的特点是T淋巴细胞渗入 末梢器官，如血管、肾脏和心脏。白介素21(IL-21)是一种促炎细胞因子 由多个T辅助细胞亚群产生，增强T辅助细胞产生IL-17A。A最近 所描述的CD4+T外周辅助细胞(TPH)亚群在以下背景下可产生IL-21 自身免疫性疾病。IL-17A是一种已知在高血压和ACT中促进免疫激活的细胞因子 直接在内皮细胞上。初步研究表明，IL-21缺陷小鼠具有迟钝的 高血压反应和IL-21的中和均可逆转内皮功能障碍并降低血液 小鼠体内的压力。这一令人信服的证据表明，IL-21是一种关键的细胞因子，推动着 适应性免疫系统与高血压的终末器官损害；然而，哪些T细胞亚群产生IL-21 目前尚不清楚IL-21是否直接作用于血管内皮细胞。该项目将(A)测试 假设TPH细胞是高血压患者IL-21的主要来源，而产生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 和(C)评估细胞因子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的潜在机制产生重要的见解 在高血压中的激活和识别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.