This study highlights the critical role of IRF8 in the development of AAA. IRF8 activation promotes the differentiation of cDC1s, which in turn recruit and activate CD8+ T cells, contributing to aortic wall degradation. The study identifies the IRF8-cDC1-CD8+ T cell axis as a key pathway in AAA progression, offering new potential therapeutic targets to inhibit disease progression.
Abstract
Abdominal aortic aneurysm (AAA) is the most common true aneurysm worldwide, and recent studies suggest that dendritic cells (DCs) play a key role in its development, though the specific subtypes and underlying mechanisms remain unclear. In this study, the role of interferon regulatory factor 8 (IRF8) in AAA is investigated by focusing on its effect on the differentiation of DC precursors into conventional type 1 dendritic cells (cDC1s). It is found significant infiltration of HLA-DR+ IRF8+ cells in human AAA tissue samples. In mice, DC-specific overexpression of Irf8 exacerbates aneurysm expansion following periadventitial elastase application, while DC-specific Irf8 deletion attenuates AAA development. Batf3
−/− mice, which lack cDC1s, exhibit AAA characteristics similar to the Irf8-deleted mice. Additionally, an increased population of activated CD8+ T cells is observed in the DC-Irf8 overexpressed mice, while the DC-Irf8 deletion mice show a decrease in these cells. Blocking antigen cross-presentation to CD8+ T cells also reduces AAA progression. Tissue microarray analysis of human aortic samples further confirms a correlation between IRF8 expression and AAA development. These findings suggest that IRF8 activation promotes cDC1 differentiation, leading to the recruitment of CD8+ T cells, which contribute to aortic wall destruction and AAA formation.
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