The Role of IL-1R1 in cell transitions in Aortic Aneurysm Pathogenesis

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Hypothesis: Our previous studies using elastase-perfusion models of abdominal aortic aneurysms (AAA) have shown that IL-1R1 KO mice have a decreased incidence and size of aneurysm formation. We have also recently shown that treatment with the IL-1 pathway inhibitor, anakinra, in both prevention and treatment studies results in significant protection from aneurysm formation in a mouse model of AAA. In the current proposal, we will investigate the role of IL-1 signaling in smooth muscle and macrophage phenotypic transitions using novel rigorous lineage tracing mouse models of abdominal aortic aneurysm (AAA) formation and to examine the mechanism of IL-1R1 signaling in AAA formation as a method to selectively determine treatment strategies to protect against AAA formation. Methods: We will use a elastase perfusion and Angiotensin II murine models of AAA coupled with rigorous smooth muscle and macrophage lineage tracing analysis in conditional IL-1 receptor 1 KO mice. Anakinra treatment will be administered via osmotic pump to determine the role of Anakinra treatment on smooth muscle cell and macrophage transitions during aneurysm formation. Aortic diameter will be measured on day 3, 7, 14, and 28. Aortic tissue will be harvested to analyze pro-inflammatory cytokine (IL-1β, TNF-α, MCP-1, IL-6, and RANTES), MMP-2 and MMP-9 activity by zymography, serine proteases (uPA, tPA and PAI-1) by western blots, elastin and collagen degradation as well as aortic smooth muscle expression by histology, and immune cell (macrophages, T cells, neutrophils, B cells) infiltration by flow cytometry. Results: Preliminary data found significant attenuation in aneurysm formation in IL-1R1 KO mice 14 days following elastase perfusion in AAA formation. Wild-type male mice administered anakinra via osmotic pump 3 days before TAA formation also exhibited decreased aortic diameter. AAA formation in IL1β and IL1R1 KO male mice display a decreased aortic diameter, decreased cytokine production (TNFα, MCP-1, IL-6 and IL-27), decreased MMP-9 expression and decreased macrophage and neutrophil infiltration compared to wild-type male mice. Finally, IL-1R1 is increased in human AAA samples versus non-aneurysmal controls via qPCR and immunohistochemistry. Conclusions: IL-1 pathway inhibition can attenuate aneurysm formation and inflammation in the topical elastase murine model of AAA. We propose to delineate the mechanism of IL-1 signaling in AAA formation using novel lineage tracing analysis in smooth muscle cell and macrophages and to examine the role of IL-1 signaling in the pathology of aneurysm formation with the overall goal to develop aneurysm treatment.