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, Xiaoxi Ju, Heidi Spratt, Dong Chuan Guo, Dianna Milewicz, Ronald Tilton, Allan R. Brasier

Research output: Contribution to journalArticle

255 Citations (Scopus)

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+CD14 hiCD11bhiF4/80- 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.

Original languageEnglish (US)
Pages (from-to)3637-3651
Number of pages15
JournalJournal of Clinical Investigation
Volume119
Issue number12
DOIs
StatePublished - Dec 1 2009

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Adventitia
Blood Vessels
Dissection
Monocytes
Interleukin-6
Macrophages
Inflammation
Aorta
Fibroblasts
CCR2 Receptors
Subcutaneous Infusions
Adoptive Transfer
Aortic Aneurysm
Chemotactic Factors
Incidence
Conditioned Culture Medium
Coculture Techniques
Matrix Metalloproteinases
Inbred C57BL Mouse
Leukocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 119, No. 12, 01.12.2009, p. 3637-3651.

Research output: Contribution to journalArticle

Tieu, BC, Lee, C, Sun, H, LeJeune, W, Recinos, A, Ju, X, Spratt, H, Guo, DC, Milewicz, D, Tilton, R & Brasier, AR 2009, 'An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice', Journal of Clinical Investigation, vol. 119, no. 12, pp. 3637-3651. https://doi.org/10.1172/JCI38308
Tieu, Brian C. ; Lee, Chang ; Sun, Hong ; LeJeune, Wanda ; Recinos, Adrian ; Ju, Xiaoxi ; Spratt, Heidi ; Guo, Dong Chuan ; Milewicz, Dianna ; Tilton, Ronald ; Brasier, Allan R. / An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 12. pp. 3637-3651.
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AU - Sun, Hong

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AU - Recinos, Adrian

AU - Ju, Xiaoxi

AU - Spratt, Heidi

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AU - Brasier, Allan R.

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