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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

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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 5

Pik3cg deficiency hinders elastase-induced AAA dilation.

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Pik3cg deficiency hinders elastase-induced AAA dilation.
(A) Representa...
(A) Representative images of immunofluorescent staining of PI3Kγ and CD68 in elastase-induced (E-induced) versus inactive elastase–induced (IE-induced) AAA from WT mice. Asterisks indicate aortic lumen. Scale bar: 100 μm. (B) Quantification of PI3Kγ in mice treated with IE (n = 7) or E (n = 7). (C) Western blot analysis suggested that PI3Kγ expression in E-induced AAA tissues was significantly increased compared with the IE group. (D) Representative photographs of WT mice and Pik3cg–/– mice subjected to IE or E treatment. Scale bar: 2 mm. (E) Pik3cg–/– mice showed a reduced AAA expansion compared with that of WT mice (n = 7 WT mice with IE, n = 7 Pik3cg–/– mice with IE, n = 7 WT with E, n = 7 Pik3cg–/– with E). (F) CD68 immunostaining in AAA tissues from WT mice and Pik3cg–/– mice after E treatment for 2 weeks. Quantification is shown on the right. Asterisks indicate aortic lumen. Scale bar: 100 μm. Data are presented as mean ± SD, and the significance was determined by unpaired, 2-tailed Student’s t test (B and C) or 2-way ANOVA followed by Bonferroni’s test (E and F). *P < 0.05, ***P < 0.001.

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