Abstract 13582: Interferon Regulatory Factor 8 Promotes Abdominal Aortic Aneurysm via Inducing Type I Conventional Dendritic Cell Differentiation

Abstract

Introduction: Abdominal aortic aneurysm (AAA) remains to be the most common true aneurysm worldwide. Previous studies identified the participation of dendritic cells (DC) in the pathogenesis of AAA. However, the detailed subtypes involved and mechanisms remain unknown. Our previous RNA-Seq data determined dramatically increased Irf8 in AAA samples, which drives DC differentiating to Type I conventional dendritic cells (cDC1). Aim: The aim of the work is to determine the role of interferon regulatory factor 8 (IRF8) in the development of AAA. Methods and Results: Murine AAA were induced via elastase infusion. The single-cell transcriptomic sequencing of CD45+ cells in murine AAA samples identified the dramatically increased cDC1. By flow cytometry, we found that the ratio of CD103 + cDC1s reached maximum at day 7. Compared with the control group, Irf8 CAG-LSL Itgax Cre mice ( Irf8 overexpression in DC) suffered significantly more severe aneurysm expansion, elastin degradation and apoptosis of smooth muscle cells, while the AAA development in Irf8 flox/flox Itgax Cre mice ( Irf8 deletion in DC) was less sharp. Batf3 -/- mice which were cDC1 depleted, showed similar characteristic in AAA expansion with Irf8 flox/flox Itgax Cre mice. The effective CD8 + T cells increased significantly in Irf8 CAG-LSL Itgax Cre mice than the control group, while decreased in Irf8 flox/flox Itgax Cre ones. Deletion of Clec9a which blocks cross-present dead-cell-associated antigens to the CD8 + T cells, also attenuated AAA development, in accordance with Irf8 flox/flox Itgax Cre mice in gross anatomy and pathology changes. Conclusion: Our findings suggest that the activation of IRF8 promotes cDC1 differentiation, which subsequently activate CD8 + T cells and contribute to destruction of the aortic-wall and AAA formation.