Cytokine mediated regulation of stress myelopoiesis in abdominal aortic aneurysm

细胞因子介导的腹主动脉瘤应激性骨髓生成的调节

• 批准号: 10305359
• 负责人: Ekaterina Koltsova
• 金额: $ 50.74万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305359
• 关键词: Abdominal Aortic Aneurysm; Affect; Age; Angiotensin II; Anti-Inflammatory Agents; Antibodies; Aorta; Apolipoprotein E; Area; Atherosclerosis; Automobile Driving; Biochemical; Biological; Biology; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cardiovascular Pathology; Cause of Death; Cell Cycle; Cell Proliferation; Cells; Cellular Metabolic Process; Cellular Stress; Collaborations; Cytokine Signaling; Data; Development; Disease; Distal; Distant; Elderly; Exhibits; Family; Gender; Generations; Genetic; Genetic Models; Hematopoiesis; Hematopoietic stem cells; Hypertension; IL27RA gene; IL6 gene; Immune; Immune mediated destruction; Immunologics; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-12; Interleukins; Knowledge; Lead; Life; Light; Mediating; Methods; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Output; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Pathway interactions; Pharmacology; Play; Population; Prevention therapy; Preventive; Production; Regulation; Research; Risk Factors; Role; Scheme; Signal Transduction; Site; Smoking; Stimulus; Stress; System; TP53 gene; Therapeutic; Work; anaerobic glycolysis; base; cytokine; disorder prevention; fitness; hematopoietic stem cell expansion; hematopoietic stem cell quiescence; in vivo; innovation; insight; macrophage; male; member; monocyte; neutrophil; novel; programs; recruit; response; therapeutic development; transcriptomics

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.

项目总结/摘要 心血管疾病是“西化”人群的主要死因。其中一个生命- 在老年人中威胁性的血管疾病是无症状的腹主动脉瘤（AAA）的形成。 免疫介导的主动脉壁破坏在AAA的发病机制中起着重要作用。 疾病细胞因子，可溶性炎症介质，有助于免疫细胞的积累和激活， 受影响的地区。虽然先前研究了几种细胞因子在AAA中的作用，但它们的拟议功能 仅限于它们在血管壁中的作用。虽然炎症和免疫细胞与AAA有关， 驱动AAA起始和进展的炎症机制仍然知之甚少。比如说， 细胞因子和AngII信号传导是否（以及如何）协同产生和招募致病性免疫细胞 代表了一个重大的知识缺口。 白细胞介素（IL）27是IL 6/IL 12家族的成员，通常被认为是抗炎药。 然而，IL 27 R信号传导在AAA中的作用从未被阐明。在这里，我们建议调查 IL 27 R信号转导在AAA发展中的调节作用及其作用的机制基础。 使用已建立的动脉粥样硬化倾向性AAA模型（Apoe-/-小鼠）， 易感遗传背景与血管紧张素II介导的疾病诱导，我们作出了意想不到的 观察到缺乏IL 27 R信号传导的小鼠（IL 27 ra-/-）表现出显著减少的IL-27受体的积累。 骨髓细胞转移到肾上动脉瘤（AAA疾病部位），从而显著降低AAA发病率， 进展我们的初步数据表明，IL 27 R信号传导对于AAA诱导AngII的能力是必不可少的。 以驱动骨髓中造血干细胞（HSC）活化和应激诱导的骨髓生成， 产生被募集到疾病部位的促进AAA的骨髓细胞。这些意料之外的发现 提示IL 27 R信号传导是AAA的关键、靶向、促炎介质，并使我们假设 IL 27 R信号通过增强HSC适应性和向骨髓谱系分化来驱动AAA， 对AngII的回应从机制上讲，我们将确定：1）IL 27 R信号如何调节HSC的“适应性”，激活 和“应激诱导的”AAA骨髓分化;和2）AAA的分子和细胞机制 这种意想不到的联系，这将揭示IL 27 R是否可以作为AAA的重要靶点 预防和治疗。我们将通过整合一系列免疫学、生物化学和分子生物学技术来实现这一目标。 生物学方法。总的来说，拟议的研究将揭示IL 27 R信号在AAA发展中的作用。 这项工作具有翻译潜力，IL 27 R信号转导可能成为预防和治疗癌症的有吸引力的候选者。 治疗方法。白细胞介素27在腹主动脉瘤发生中的生物学作用及应激性骨髓生成的研究 将开辟新的途径来研究骨髓反应与疾病相关性之间的关系， 刺激和心血管病理学。