Novel Role of Interleukin-17 in Sympathetic Activation in Heart Failure

心力衰竭（HF）是65岁以上老年人住院和死亡的最常见原因， 随着人口老龄化，统计数据预计会增长。HF对我们医疗保健的社会经济影响 系统是巨大的。因此，开发治疗HF的创新方法是一项顶级研究 要务尽管炎症和免疫激活与HF的病理生理学有关， 在过去的二十年里，针对这一机制的新药物的开发进展 是停滞不前，特别是考虑到几个抗细胞因子的临床试验，针对单一的效应细胞因子在 HF的外周表现没有产生临床益处。显然，炎症机制 HF的发病机制尚未受到挑战。研究大脑作用的拟议项目 白细胞介素（IL）-17 A（以前称为IL-17）在促进中枢炎症、交感神经激活和 心功能不全将有助于更好地了解HF的炎症机制 并提供了治疗这种毁灭性疾病的新的抗细胞因子方法。研究计划是 基于IL-17 A的内在特性和我们令人信服的初步数据而开发的：1）IL-17 A是一种kay， 炎症调节剂桥接免疫反应和组织炎症; 2）它促进 脑和外周组织和细胞中的广谱炎性介质; 3）全身性和 IL-17 A的中枢给药诱导了血压、心率和心率的显著和持久的增加， 肾交感神经活性达到其他炎症前细胞因子未见的水平; 4）IL-17 A水平 在血浆、脑脊液和下丘脑室旁核（PVN，一个关键的心血管系统）中， 和脑的自主神经中枢）在HF大鼠模型中比在假手术（Sham）动物中更高;和5） 其受体IL-17 RA在PVN中高度表达，在HF中显著上调。使用多方面的 方法包括电生理学、分子生物学、免疫细胞化学、药理学、生物化学 本项目将：1）确定IL-17 A在促进中枢神经系统的作用， HF中的炎症; 2）确定IL-17 A触发交感神经激活的炎症机制 3）评估单独或联合靶向IL-17 A信号传导的中枢干预的保护作用。 与HF中的其他细胞因子组合。这项拟议中的研究将针对炎症的主要调节因子 而不是单一效应细胞因子作为治疗HF的新型抗细胞因子策略，并考虑 因此，本发明提供了多种细胞因子的协同作用作为改善HF的潜在更有效的手段。的 所提出的研究将表征脑IL-17 A在交感神经激活中的先前未被认识的作用， 测试其作为治疗HF心功能不全的靶点的潜力。该研究项目的完成将 为HF的抗炎治疗策略提供了重要的见解， 治疗其他心血管疾病如高血压和代谢疾病如肥胖或糖尿病。

Heart failure (HF) is the most common reason for hospitalization and death among those older than 65 years, and statistic is projected to grow as our population ages. The socioeconomic impact of HF on our health care system is enormous. Development of innovative approaches to the treatment of HF is therefore a top research priority. Although inflammation and immune activation have been implicated in the pathophysiology of HF over the past two decades, the progress for development of new pharmaceutical agents targeting this mechanism was stagnant, especially given that several anti-cytokine clinical trials targeting a single effector cytokine at the peripheral manifestations of HF did not produce clinical benefits. Obviously, the inflammatory mechanisms underlying the pathogenesis of HF have not been challenged. The proposed project studying a role of brain interleukin (IL)-17A (previously known as IL-17) in advancing central inflammation, sympathetic activation and cardiac dysfunction will address the need for a better understanding of the inflammatory mechanisms in HF and provide a novel anti-cytokine approach in treating this devastating disease. The research plan was developed based on the intrinsic property of IL-17A and our compelling preliminary data: 1) IL-17A is a kay inflammatory regulator bridging immune responses and tissue inflammation; 2) It boosts the expression of a broad spectrum of inflammatory mediators in the brain and in the peripheral tissue and cells; 3) Systemic and central administration of IL-17A induced dramatic and long-lasting increases in blood pressure, heart rate and renal sympathetic nerve activity to the levels not seen by other pre-inflammatory cytokines; 4) levels of IL-17A in the plasma, cerebrospinal fluid, and paraventricular nucleus of hypothalamus (PVN, a key cardiovascular and autonomic center of the brain) are higher in a rat model of HF vs. in sham-operated (Sham) animals; and 5) Its receptor, IL-17RA, is highly expressed in the PVN and substantially upregulated in HF. Using a multifaceted approach including electrophysiology, molecular biology, immunocytochemistry, pharmacology, biochemistry and neuroscience in Sham and HF rats, this project will: 1) identify the role of IL-17A in advancing central inflammation in HF; 2) determine the inflammatory mechanisms whereby IL-17A triggers sympathetic activation in HF; 3) evaluate the protective effect of central interventions targeting the IL-17A signaling, alone or in combination with other cytokines in HF. The proposed research will target a master regulator of inflammation rather than a single effector cytokine as a novel anti-cytokine strategy in treating HF, and consider the synergistic actions of multiple cytokines as a potentially more effective means of ameliorating HF. The proposed studies will characterize a previously unrecognized role of brain IL-17A in sympathetic activation and test its potential as a target in treating cardiac dysfunction of HF. Completion of this research project will provide important insights into the anti-inflammation therapeutic strategy in HF and may carry the implication for other cardiovascular disorders like hypertension and metabolic diseases like obesity or diabetes.