Role of ILC2 and eosinophils in abdominal aortic aneurysm

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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.