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: 10322053
• 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/10322053
• 关键词: Abdominal Aortic Aneurysm; Adhesions; Adoptive Transfer; Affect; Allergic; Angiotensin II; Antibodies; Apolipoprotein E; Apoptosis; Atherosclerosis; Attenuated; Blood; Bone Marrow; Bone Marrow Transplantation; Cardiovascular Diseases; Cations; 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; Mediating; Mediator of activation protein; 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; macrophage; 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.

腹部主动脉瘤（AAA）影响美国和全球一般人群的0.5〜3.2％。除了 调整生活方式，开放手术和血管内支架移植仍然是主要治疗方法 已经开发出非侵入性药物。第2组先天淋巴样细胞（ILC2）是先天的 尽管它们的总数几乎无法检测 总淋巴细胞）。关于心血管疾病（CVD）的ILC2的信息有限，尽管 从ILC2缺陷小鼠中移植骨髓的移植促进了动脉粥样硬化。嗜酸性粒细胞（EOS）也是 过敏性传感器或 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 风险因素以及CVD患病率和死亡率。然而其他研究报告了血液EOS计数和ECP的减少 重大不良简历事件患者的水平。因此，EOS在人类CVD中的作用也仍然存在 未安排。我们的初步研究表明，rorafl/sgil7racre小鼠（ILC2KO）的ILC2缺乏症或 Diphtheria Toxin（DTX）诱导的ICOSFL-DTR-FL/+ CD4CRE/+小鼠（ILC2DTX）中诱导的ILC2部署增加了增长 Aortic Capo4损伤引起的AAA。相反，ILC2或EOS自适应转移至ILC2KO小鼠减少 AAA增长。进一步的研究表明，ILC2KO小鼠缺乏脾和血液EOS和血浆IL5， 控制骨髓和EOS迁移中EOS发育的必需ILC2类型2细胞因子 外围。给药小鼠重组IL5在ILC2KO小鼠中恢复了血液EOS损失，提供了 ILC2活性在阻断AAA增长方面的机理解释并提出同时有益作用 主动脉壁中的EOS和ILC2。在AAA患者中，我们检测到的血液EOS计数明显高于 没有AAA的患者。血液EOS计数是人类AAA的重要危险因素。 EO在人和小鼠AAA病变中积累。然而，∆Dblgata小鼠的EOS缺乏加速了AAA 生长。从野生型（WT）小鼠或小鼠重组EOS给药的供体EOS的收养转移 阳离子蛋白MEAR1降低了∆Dblgata小鼠的AAA生长。机械研究提出了EOS的作用 在促进M2巨噬细胞极化和减少IFN-γ诱导的中，EOS衍生的IL4和MEAR1在 Ly6CHI单核细胞膨胀，巨噬细胞NF-κB激活和中性粒细胞内皮粘合剂。中央 假设是ILC2释放2型细胞因子，例如IL5，以促进骨中的EO​​S发育 骨髓和EOS在主动脉壁上积累，EOS在保护中执行与ILC2相似的作用 AAA病变生长的主动脉壁。我们提出了两个目的，以检查ILC2是如何以及如何促进或 减弱实验AAA生长并探索EOS介导的主动脉保护机制 AAA开发。