Role of ILC2 and eosinophils in abdominal aortic aneurysm

腹主动脉瘤（AAA）影响美国和全球0.5%~3.2%的普通人群。除了 调整生活方式、开放手术和血管内支架移植术仍是主要的治疗方法， 已经被用于开发非侵入性药物。第2组先天性淋巴样细胞（ILC 2）是先天性的 淋巴细胞在肥胖中起重要作用，尽管它们的总数几乎检测不到（<0.1%的 总淋巴细胞）。关于心血管疾病（CVD）中ILC 2的信息有限，尽管 ILC 2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，在过敏性致敏后在血液或炎症部位积聚，或 寄生虫感染血EOS计数和EOS阳离子蛋白（ECP）水平与主要CV呈正相关 危险因素以及心血管疾病患病率和死亡率。然而，其他研究报告血液EOS计数和ECP减少 发生重大CV不良事件的患者中的水平。因此，EOS在人类CVD中的作用仍然存在。 不安我们的初步研究表明，Rorafl/sgIL 7 raCre小鼠（ILC 2KO）或Rorafl/sgIL 7 raCre小鼠中的ILC 2缺陷可导致IL-2水平降低。 白喉毒素（DTX）诱导的Icosfl-DTR-fl/+ Cd 4Cre/+小鼠（ILC 2DTX）中ILC 2消耗增加了 主动脉周围CaPO 4损伤诱发AAA。相比之下，ILC 2或EOS过继转移至ILC 2KO小鼠减少了 AAA级增长进一步的研究表明，ILC 2KO小鼠缺乏脾脏和血液EOS和血浆IL 5， 一种必需的ILC 2 2型细胞因子，控制骨髓中EOS的发育和EOS迁移， 外围设备。施用小鼠重组IL 5恢复了ILC 2KO小鼠中的血液EOS损失，提供了一种新的治疗方法。 ILC 2活性在阻断AAA生长中的机制解释，并提示ILC 2的同时有益作用。 主动脉壁EOS和ILC 2。在AAA患者中，我们检测到血液EOS计数显著高于 没有AAA的患者血EOS计数是人AAA的显著和独立的危险因素。 EOS在人和小鼠AAA病变中积累。然而，Eos缺陷在Eos dblGATA小鼠中加速AAA， 增长从野生型（WT）小鼠连续转移供体EOS或给予小鼠重组EOS 阳离子蛋白mEar 1减少了AddblGATA小鼠的AAA生长。机制研究表明EOS的作用 和EOS衍生的IL 4和mEar 1促进M2巨噬细胞极化和减少IFN-γ诱导的 Ly 6 Chi单核细胞扩增、巨噬细胞NF-κB活化和中性粒细胞内皮粘附。中央 假设ILC 2释放2型细胞因子，如IL 5，以促进骨中EOS的发育， 骨髓和EOS积聚在主动脉壁中，其中EOS发挥与ILC 2类似的作用， 主动脉瘤病变生长引起的主动脉壁。我们提出了两个目的，以研究国际法委员会第二届会议是否以及如何促进或 减弱实验性AAA生长，并探索EOS介导的主动脉保护机制， AAA发展。

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.