Cytokine mediated regulation of stress myelopoiesis in abdominal aortic aneurysm

项目摘要/摘要 心血管疾病是“西方化”人群死亡的主要原因。生命中的一种- 威胁老年人的血管疾病是无症状的腹主动脉瘤(AAA)形成。 AAA时免疫介导的主动脉壁破坏在AAA的发病机制中起重要作用 疾病。细胞因子，可溶的炎症介质，有助于免疫细胞的聚集和激活 受影响的地区。虽然之前已经研究了几种细胞因子在AAA中的作用，但它们提出的功能 仅限于他们在血管壁上的行动。虽然炎症和免疫细胞与AAA有关，但 推动AAA发生和发展的炎症机制仍然知之甚少。例如, 细胞因子和血管紧张素Ⅱ信号是否(以及如何)协同产生和招募致病免疫细胞 骨髓的数量代表了知识上的一大差距。 白介素27是白介素6/白介素12家族的一员，传统上被认为是一种抗炎药物 细胞因子；然而，IL27R信号在AAA中的作用从未被阐明。在这里，我们建议调查 IL27R信号在AAA发生中的调控作用及其机制基础。 使用已建立的易患动脉粥样硬化的AAA模型(APOE-/-小鼠)，该模型结合了 易感遗传背景与血管紧张素II介导的疾病诱导，我们做出了意想不到的 观察到缺乏IL27R信号的小鼠(IL27ra-/-)表现出显著的减少 髓系细胞到达肾上动脉(AAA病部位)，从而显著降低AAA的发病率和 进步。我们的初步数据表明，IL27R信号转导通路对于AAA诱导的血管紧张素转换酶的能力是必不可少的 促进造血干细胞(HSC)的激活和应激诱导的骨髓生成， 产生促进AAA的髓系细胞，这些细胞被招募到疾病部位。这些出乎意料的发现 提示IL27R信号是AAA的关键、靶向、促炎介质，并引导我们提出假说 IL27R信号通过增强HSC的适合性和向髓系的分化来驱动AAA 对安吉的回应。从机制上讲，我们将确定：1)IL27R信号如何调节HSC的“适合性”，激活 和“应激诱导”AAA的髓系分化；以及2)潜在的分子和细胞机制。 这种意想不到的联系，将揭示IL27R是否可能被用作AAA的重要目标 预防和治疗。我们将通过整合一系列免疫学、生化和分子生物学来实现这一点 生物学方法。总体而言，拟议的研究将揭示IL27R信号在AAA发展中的作用。 这项工作具有翻译潜力，IL27R信号可能成为预防和治疗的有吸引力的候选信号。 治疗方法。IL-27在HSC中的生物学作用及其在AAA发育过程中应激性骨髓生成的研究 将为研究骨髓反应与疾病之间的关系开辟新途径 刺激与心血管病理学。

PROJECT SUMMARY/ABSTRACT Cardiovascular diseases are a major cause of death among “westernized” populations. One of the life- threatening vascular conditions in the elderly is an asymptomatic formation of aortic abdominal aneurysm (AAA). Immune-mediated destruction of the aortic wall during AAA plays a significant role in the pathogenesis of this disease. Cytokines, soluble mediators of inflammation, contribute to immune cell accumulation and activation in the affected area. While role of several cytokines in AAA was previously investigated, their proposed function was limited to their action in the vessel wall. While inflammation and immune cells are implicated in the AAA, the inflammatory mechanisms driving AAA initiation and progression are still poorly understood. For example, whether (and how) cytokines and AngII signaling collaborate to produce and recruit pathogenic immune cells out of bone marrow represents a major gap in knowledge. Interleukin (IL)27, a member of the IL6/IL12 family, is conventionally regarded as an anti-inflammatory cytokine; however, the role of IL27R signaling in AAA has never been elucidated. Here we propose to investigate the role of IL27R signaling in regulation of AAA development, and the mechanistic basis underlying its effect. Using an established atherosclerosis-prone model predisposing to AAA (Apoe-/- mice) that combines a susceptible genetic background with Angiotensin II mediated induction of disease, we made the unanticipated observation that mice lacking IL27R signaling (IL27ra-/-) exhibited a remarkable reduction in the accumulation of myeloid cells to the suprarenal aortas (the AAA disease site), and thus significantly reduced AAA incidence and progression. Our preliminary data suggest that IL27R signaling is essential for the ability of AAA-inducing AngII to drive hematopoietic stem cells (HSC) activation and stress induced myelopoiesis in the bone marrow, which generates the AAA-promoting myeloid cells that are recruited to the disease site. These unanticipated findings implicate IL27R signaling as a critical, targetable, pro-inflammatory mediator of AAA, and leads us to hypothesize that IL27R signaling drives AAA by potentiating HSC fitness and differentiation toward myeloid lineages in response to AngII. Mechanistically, we will determine: 1) how IL27R signaling regulates HSC “fitness,” activation and “stress-induced” myeloid differentiation in AAA; and 2) the molecular and cellular mechanisms underlying this unexpected connection, which will reveal whether IL27R may be leveraged as a significant target for AAA prevention and therapy. We will do so by integrating an array of immunological, biochemical and molecular biological methods. Overall, the proposed research will uncover the role of IL27R signaling in AAA development. This work has translational potential and IL27R signaling may become an attractive candidate for preventive and therapeutic approaches. Studies on the biology of IL27 within HSC and stress myelopoiesis in AAA development will open new avenues to study the relationship between the bone marrow response to the disease-relevant stimuli and cardiovascular pathology.