An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice
Brian C. Tieu, Chang Lee, Hong Sun, Wanda LeJeune, Adrian Recinos 3rd, Xiaoxi Ju, Heidi Spratt, Dong-Chuan Guo, Dianna Milewicz, Ronald G. Tilton, Allan R. Brasier
Brian C. Tieu, Chang Lee, Hong Sun, Wanda LeJeune, Adrian Recinos 3rd, Xiaoxi Ju, Heidi Spratt, Dong-Chuan Guo, Dianna Milewicz, Ronald G. Tilton, Allan R. Brasier
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Research Article

An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice

Abstract

Vascular inflammation contributes to cardiovascular diseases such as aortic aneurysm and dissection. However, the precise inflammatory pathways involved have not been clearly defined. We have shown here that subcutaneous infusion of Ang II, a vasopressor known to promote vascular inflammation, into older C57BL/6J mice induced aortic production of the proinflammatory cytokine IL-6 and the monocyte chemoattractant MCP-1. Production of these factors occurred predominantly in the tunica adventitia, along with macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic dissections. In contrast, a reduced incidence of dissections was observed after Ang II infusion into mice lacking either IL-6 or the MCP-1 receptor CCR2. Further analysis revealed that Ang II induced CCR2+CD14hiCD11bhiF4/80– macrophage accumulation selectively in aortic dissections and not in aortas from Il6–/– mice. Adoptive transfer of Ccr2+/+ monocytes into Ccr2–/– mice resulted in selective monocyte uptake into the ascending and suprarenal aorta in regions of enhanced ROS stress, with restoration of IL-6 secretion and increased incidence of dissection. In vitro, coculture of monocytes and aortic adventitial fibroblasts produced MCP-1– and IL-6–enriched conditioned medium that promoted differentiation of monocytes into macrophages, induced CD14 and CD11b upregulation, and induced MCP-1 and MMP-9 expression. These results suggest that leukocyte-fibroblast interactions in the aortic adventitia potentiate IL-6 production, inducing local monocyte recruitment and activation, thereby promoting MCP-1 secretion, vascular inflammation, ECM remodeling, and aortic destabilization.

Authors

Brian C. Tieu, Chang Lee, Hong Sun, Wanda LeJeune, Adrian Recinos 3rd, Xiaoxi Ju, Heidi Spratt, Dong-Chuan Guo, Dianna Milewicz, Ronald G. Tilton, Allan R. Brasier

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Figure 2

Aortic macrophages in WT mice display different phenotypes in response to Ang II.

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Aortic macrophages in WT mice display different phenotypes in response t...
(A) Cytospin preparation of dissociated aortic tissue stained with H&E. Scale bars: 150 μm (left), 50 μm (right) (original magnification: ×200 [left]; ×400 [right]). (B) Dissociated aortic cells were gated on CD14 (top left); histogram with isotype control (gray) is shown at bottom left. CD14+ cells were separated into CD14+CD11b+ and CD14+CD11b– cells. CD11b+ cells were confirmed by histogram as compared with isotype control. CD14+CD11b+ cells were F4/80+, while CD14+CD11b– cells were F4/80–. CD14+CD11b+F4/80+ were backgated to reveal the macrophage population (red contour circles, top right). Immunofluorescence staining for macrophages (CD11b+) shows adventitial localization. Original magnification, ×200. (C) CD14+CD11b+F4/80+ macrophages present in sham-treated aortas of WT mice are recruited by Ang II treatment. Macrophages in aortic dissections are increased in number but lack F4/80. (D) Histograms comparing expression of CD14, CD11b, and F4/80 on macrophage populations in sham-infused aortas (blue curve), Ang II–infused aortas (green curve), and Ang II–infused aortas with aortic dissection (red curve). (E) Ang II recruits CCR2+ macrophages. Far left: Secondary Ab (2 Aby). Middle panels: CD14+CD11b+ macrophages were gated in sham- and Ang II–infused aortas and identified as CCR2+CD11b+ (red, right panels).