An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice
| Autor: | Dongchuan Guo, Ronald G. Tilton, Xiaoxi Ju, Brian C. Tieu, Hong Sun, Chang Lee, Adrian Recinos, Dianna M. Milewicz, Wanda S. LeJeune, Heidi Spratt, Allan R. Brasier |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Pathology medicine.medical_specialty CCR2 Receptors CCR2 CD14 Biology Proinflammatory cytokine Mice Aortic aneurysm Adventitia medicine Animals Humans Macrophage Chemokine CCL2 DNA Primers Inflammation Mice Knockout Aortic dissection Base Sequence Interleukin-6 Angiotensin II Macrophages Monocyte General Medicine medicine.disease Adoptive Transfer Coculture Techniques Aortic Aneurysm Mice Inbred C57BL Aortic Dissection Disease Models Animal medicine.anatomical_structure Connective Tissue Immunology cardiovascular system Signal Transduction Research Article |
| Zdroj: | Journal of Clinical Investigation. 119:3637-3651 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci38308 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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