Role of ILC2 and eosinophils in abdominal aortic aneurysm

ILC2 和嗜酸性粒细胞在腹主动脉瘤中的作用

• 批准号: 10538557
• 负责人: GUO-PING SHI
• 金额: $ 68.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538557
• 关键词: Abdominal Aortic Aneurysm; Acceleration; Adhesions; Adoptive Transfer; Affect; Allergic; Angiotensin II; Antibodies; Aorta; Apolipoprotein E; Apoptosis; Atherosclerosis; Attenuated; Blood; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Cessation of life; Development; Diphtheria Toxin; Endothelium; Eosinophil cationic protein; Event; General Population; Growth; Human; Human Activities; IL4 gene; IL5 gene; Immune; Inflammation; Infusion procedures; Injury; Interferon Type II; Interleukin-10; Interleukin-13; Interleukin-5; Lesion; Life Style; Link; Lymphocyte; Lymphoid Cell; Macrophage; Mediating; Mediator; Modeling; Molecular; Mus; Obesity; Operative Surgical Procedures; Parasitic infection; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Play; Prevalence; Proteins; Recombinants; Reporting; Risk Factors; Role; Site; Stents; Testing; Wild Type Mouse; abdominal wall; angiogenesis; blood pressure control; cell type; cytokine; eosinophil; migration; monocyte; mortality; mouse development; neutrophil; response; smoking cessation; subcutaneous

Abdominal aortic aneurysm (AAA) affects 0.5~3.2% of the general populations in US and worldwide. Besides adjusting lifestyle, open surgery and endovascular stent grafting remain the main treatments, though attempts have been made to develop non-invasive medications. Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that play essential role in obesity, although their total numbers are nearly undetectable (<0.1% of total lymphocytes). Limited information is available regarding ILC2 in cardiovascular diseases (CVD), although transplantation of bone-marrow from ILC2-deficient mice promoted atherosclerosis. Eosinophils (EOS) are also innate immune cells that accumulate in blood or at the site of inflammation after allergic sensitization or parasite infection. Blood EOS counts and EOS cationic protein (ECP) level associate positively with major CV risk factors and CVD prevalence and mortality. Yet other studies reported reduced blood EOS counts and ECP level in patients with major adverse CV events. Therefore, the role of EOS in human CVD also remains unsettled. Our preliminary studies demonstrated that ILC2 deficiency in Rorafl/sgIL7raCre mice (ILC2KO) or diphtheria toxin (DTX)-induced ILC2 depletion in Icosfl-DTR-fl/+Cd4Cre/+ mice (ILC2DTX) increased the growth of peri-aortic CaPO4 injury-induced AAA. In contrast, adoptive transfer of ILC2 or EOS to ILC2KO mice reduced AAA growth. Further study showed that ILC2KO mice were deficient in splenic and blood EOS and plasma IL5, an essential ILC2 type-2 cytokine that controls EOS development in the bone marrow and EOS migration to the peripheral. Administration of mouse recombinant IL5 recovered blood EOS loss in ILC2KO mice, providing a mechanistic explanation of ILC2 activity in blocking AAA growth and suggesting a concurrent beneficial role of EOS and ILC2 in the aortic wall. In AAA patients, we detected significantly higher blood EOS counts than in patients without AAA. Blood EOS counts served as a significant and independent risk factor of human AAA. EOS accumulated in human and mouse AAA lesions. Yet, EOS deficiency in ∆dblGATA mice accelerated AAA growth. Adoptive transfer of donor EOS from wild-type (WT) mice or administration of mouse recombinant EOS cationic protein mEar1 reduced AAA growth in ∆dblGATA mice. Mechanistic studies suggested a role for EOS and EOS-derived IL4 and mEar1 in promoting M2 macrophage polarization and in reducing IFN-γ-induced Ly6Chi monocyte expansion, macrophage NF-κB activation, and neutrophil endothelium adhesion. The central hypothesis is that ILC2 release type-2 cytokines, such as IL5 to promote EOS development in the bone- marrow and EOS accumulation in the aortic wall where EOS exert a similar role to that of ILC2 in protecting aortic wall from AAA lesion growth. We propose two Aims to examine whether and how ILC2 promote or attenuate experimental AAA growth and to explore EOS-mediated aortic protective mechanisms in response to AAA development.

腹主动脉瘤(AAA)在美国和世界范围内占总人口的0.5%~3.2%。此外 调整生活方式、开放手术和血管内支架植入术仍然是主要的治疗方法，尽管尝试 已经被用来开发非侵入性药物。第二组先天淋巴样细胞(ILC2)是先天的 在肥胖中扮演重要角色的淋巴细胞，尽管它们的总数几乎检测不到(&lt；0.1% 淋巴细胞总数)。关于ILC2在心血管疾病(CVD)中的信息有限，尽管 来自ILC2基因缺陷小鼠的骨髓移植促进了动脉粥样硬化。嗜酸性粒细胞(EOS)也是 先天免疫细胞在过敏或过敏后聚集在血液或炎症部位的天然免疫细胞 寄生虫感染。血液EOS计数和EOS阳离子蛋白(ECP)水平与主要CV呈正相关 危险因素与心血管疾病患病率和死亡率的关系。然而，其他研究报告称，血液EOS计数和ECP减少 有主要不良心血管事件的患者的水平。因此，EOS在人类CVD中的作用也仍然存在 动荡不安。我们的初步研究表明，Rorafl/sgIL7raCre小鼠(ILC2KO)的ILC2缺陷或 白喉毒素(DTX)诱导的Icosfl-DTR-fl/+CD4Cre/+小鼠ILC2耗竭(ILC2DTX)促进小鼠生长 腹主动脉周围CaPO4损伤诱导AAA。相反，ILC2或EOS过继转移到ILC2KO小鼠的次数减少 AAA增长。进一步研究表明，ILC2KO小鼠存在脾、血EOS和血浆IL5缺乏， 一种基本的ILC2-2型细胞因子，控制骨髓EOS的发育和EOS迁移到 外围设备。给小鼠重组IL5可恢复ILC2KO小鼠的EOS失血，提供一种 ILC2在阻断AAA生长中的作用的机制解释和提示同时有益的作用 主动脉壁有Eos和ILC2表达。在AAA患者中，我们检测到的血液EOS计数显著高于 无AAA的患者。血EOS计数是人类AAA的重要独立危险因素。 Eos在人和小鼠的AAA损伤中积聚。然而，∆dblGATA小鼠的EOS缺乏加速了AAA 成长。过继转移野生型(WT)小鼠供体EOS或注射小鼠重组EOS 阳离子蛋白mEar1减少了∆dblGATA小鼠的aaa生长。机械论研究表明了EOS的作用 EOS来源的IL-4和mEar1促进M2巨噬细胞极化和降低干扰素-γ诱导的 Ly6chi单核细胞扩张，巨噬细胞NF-κB活化，中性粒细胞内皮细胞黏附。中环 假说是ILC2释放2型细胞因子，如IL5，以促进骨中EOS的发育。 EOS在主动脉壁中积聚骨髓和EOS，其中EOS发挥与ILC2相似的保护作用 主动脉壁由AAA病变生长而来。我们提出两个目标来研究ILC2是否以及如何促进或 抑制实验性AAA生长及探讨EOS介导的主动脉保护机制 AAA级发展。