Mechanism of local IL-6 production and its role in accelerating vascular inflammation leading to aortic diseases

Vascular inflammation plays a significant role in aortic diseases and involves enhanced recruitment and local activation of circulating monocytes along with cytokine production, but the mechanisms responsible for these processes are unclear. The cytokine interleukin-6 (IL-6) is highly induced in aortic aneurysm and dissection and significantly increases the risk of aneurysm rupture and mortality due to cardiovascular diseases; however, it remains unknown where and how IL-6 is produced in the vascular wall and how it contributes to disease exacerbation. Using an Ang II-infusion mouse model, we found that 6 days of subcutaneous Ang II infusion into aged C57BL/6J mice induced aortic IL-6 and MCP-1 predominantly in the tunica adventitia. Likewise, IL-6 was detected mostly in the adventitia of sporadic aortic dissections in humans. There was concomitant macrophage recruitment, adventitial expansion, and development of thoracic and suprarenal aortic aneurysms and dissections in treated wild-type mice. In contrast, no dissections were produced with infusion into IL-6-/- or CCR2-/- mice over the same time period along with significantly reduced inductions of aortic IL-6 and MCP-1. Using flow cytometric quantification of aortic cellular constituents, we found that Ang II induced CCR2+ macrophage accumulation of a specific CD14hiCD11bhiF4/80- phenotype selectively in aortic dissections and not in aortas from IL-6-/- mice, which were CD14loCD11bloF4/80+. Adoptive transfer of CCR2+/+ monocytes into CCR2-/- mice resulted in selective monocyte uptake into the thoracic and suprarenal aorta with restoration of IL-6 and MCP-1 secretion and increased incidence of dissection. To elucidate a source of IL-6, we demonstrated that aortic adventitial fibroblasts (AoAFs) highly produce IL-6 and MCP-1 and Ang II treatment increased their expression. Ang II and monocytes stimulated AoAF proliferation also. In addition, coculture of monocytes and AoAFs strongly potentiated MCP-1 and IL-6, which differentiated monocytes to macrophages and up-regulated CD14 and CD11b as well as induced MCP-1 and MMP-9 expression. These results suggest that AoAFs are a source of IL-6 and that a leukocyte-fibroblast interaction in the aortic adventitia potentiates its production, leading to promotion of local monocyte recruitment and activation, thereby accelerating vascular inflammation, ECM remodeling and aortic destabilization.