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.

腹主动脉瘤 (AAA) 影响美国和全球 0.5~3.2% 的普通人群。 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，但尝试 已用于开发非侵入性药物。第 2 类先天淋巴细胞 (ILC2) 是先天性的。 淋巴细胞在肥胖中发挥重要作用，尽管其总数几乎检测不到（<0.1% 尽管关于 ILC2 在心血管疾病 (CVD) 中的作用的信息有限。 ILC2 缺陷小鼠的骨髓移植也会促进动脉粥样硬化。 过敏致敏或过敏后在血液中或炎症部位积聚的先天免疫细胞 血液 EOS 计数和 EOS 阳离子蛋白 (ECP) 水平与主要 CV 呈正相关。 其他研究报告称，血液 EOS 计数和 ECP 有所减少。 因此，EOS 在人类 CVD 中的作用仍然存在。 我们的初步研究表明 Rorafl/sgIL7raCre 小鼠 (ILC2KO) 或 ILC2 缺陷。 Icosfl-DTR-fl/+Cd4Cre/+ 小鼠 (ILC2DTX) 中白喉毒素 (DTX) 诱导的 ILC2 耗竭增加了白喉毒素 (DTX) 的生长 相反，ILC2 或 EOS 过继转移至 ILC2KO 小鼠中主动脉周围 CaPO4 损伤诱导的 AAA 减少。 进一步研究表明，ILC2KO 小鼠的 AAA 生长缺乏脾脏和血液 EOS 以及血浆 IL5， 一种重要的 ILC2 2 型细胞因子，控制骨髓中 EOS 的发育和 EOS 迁移 小鼠重组 IL5 的施用恢复了 ILC2KO 小鼠的血液 EOS 损失，提供了 ILC2 活性阻断 AAA 生长的机制解释并表明 在 AAA 患者中，我们检测到主动脉壁中的 EOS 和 ILC2 明显高于 AAA 患者。 没有 AAA 的患者的血液 EOS 计数是人类 AAA 的一个重要且独立的危险因素。 EOS 在人类和小鼠 AAA 病变中积累，然而，ΔdblGATA 小鼠中 EOS 缺乏会加速 AAA。 来自野生型 (WT) 小鼠的供体 EOS 的过继转移或小鼠重组 EOS 的施用。 阳离子蛋白 mEar1 减少 ΔdblGATA 小鼠的 AAA 生长 机制研究表明 EOS 的作用。 EOS 衍生的 IL4 和 mEar1 促进 M2 巨噬细胞极化并减少 IFN-γ 诱导的 Ly6Chi 单核细胞扩增、巨噬细胞 NF-κB 激活和中性粒细胞内皮粘附 中枢。 假设ILC2释放2型细胞因子，例如IL5，以促进骨中EOS的发育。 骨髓和 EOS 在主动脉壁中积聚，其中 EOS 发挥与 ILC2 相似的保护作用 我们提出了两个目标来检查 ILC2 是否以及如何促进或促进。 减弱实验性 AAA 生长并探索 EOS 介导的主动脉保护机制 AAA级发展。