IRF5 governs macrophage adventitial infiltration to fuel abdominal aortic aneurysm formation
Yidong Wang, … , Zhejun Cai, Meixiang Xiang
Yidong Wang, … , Zhejun Cai, Meixiang Xiang
Published January 4, 2024
Citation Information: JCI Insight. 2024;9(3):e171488. https://doi.org/10.1172/jci.insight.171488.
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Research Article Vascular biology

IRF5 governs macrophage adventitial infiltration to fuel abdominal aortic aneurysm formation

Abstract

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the expansion of the aortic wall. One of the most significant features is the infiltration of macrophages in the adventitia, which drives vasculature remodeling. The role of macrophage-derived interferon regulatory factor 5 (IRF5) in macrophage infiltration and AAA formation remains unknown. RNA sequencing of AAA adventitia identified Irf5 as the top significantly increased transcription factor that is predominantly expressed in macrophages. Global and myeloid cell–specific deficiency of Irf5 reduced AAA progression, with a marked reduction in macrophage infiltration. Further cellular investigations indicated that IRF5 promotes macrophage migration by direct regulation of downstream phosphoinositide 3-kinase γ (PI3Kγ, Pik3cg). Pik3cg ablation hindered AAA progression, and myeloid cell–specific salvage of Pik3cg restored AAA progression and macrophage infiltration derived from Irf5 deficiency. Finally, we found that IRF5 and PI3Kγ expression in the adventitia is significantly increased in patients with AAA. These findings reveal that the IRF5-dependent regulation of PI3Kγ is essential for AAA formation.

Authors

Yidong Wang, Zhenjie Liu, Shen Song, Jianfang Wang, Chunna Jin, Liangliang Jia, Yuankun Ma, Tan Yuan, Zhejun Cai, Meixiang Xiang

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Figure 4

IRF5 promotes macrophage migration via PI3Kγ.

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IRF5 promotes macrophage migration via PI3Kγ. (A) Venn diagram showing t...
(A) Venn diagram showing the overlapping genes among differentially expressed genes (DEGs) between WT and Irf5–/– mice, migration-related genes, macrophage highly expressed genes, and genes with a potential IRF5 binding site. (B) Heatmap of the 15 overlapping genes in AAA tissues from WT and Irf5–/– mice. (C and D) Macrophages from Irf5fl/fl and Irf5ΔMΦ mice were treated or not with TNF-α (50 ng/mL). The mRNA (C, n = 7) and protein (D, n = 4) levels of PI3Kγ were decreased in macrophages with IRF5 deletion. (E) Bone marrow–derived macrophages (BMDMs) stimulated with TNF-α (50 ng/mL) or not for 2 hours were collected, and ChIP assays were conducted (n = 6). Chromatin was immunoprecipitated and assessed by PCR analysis to determine the binding site on the Pik3cg promoter. (F) Dual-luciferase assays indicated that the Irf5 expression plasmid transfected into HEK293T cells increased luciferase activity of Pik3cg promoter reporter plasmids, and luciferase activity was reduced when Pik3cg promoter reporter plasmids harbored the deletion of nt –1060 to –1047 (n = 6). (G and H) Migratory abilities of macrophages from Irf5fl/fl, Irf5ΔMΦ, and Pik3cgMΦ+ Irf5ΔMΦ mice were measured by wound healing (G) and Transwell (H) assays (n = 9). Excessive PI3Kγ expression promoted macrophage migration. Scale bar: 50 μm. Data are presented as mean ± SD, and the significance was determined by 2-way ANOVA followed by Bonferroni’s test (C–E) or 1-way ANOVA followed by Bonferroni’s test (F–H). *P < 0.05, **P < 0.01, ***P < 0.001.