An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice.
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.
Tieu
Brian C
BC
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Lee
Chang
C
Sun
Hong
H
Lejeune
Wanda
W
Recinos
Adrian
A
Ju
Xiaoxi
X
Spratt
Heidi
H
Guo
Dong-Chuan
DC
Milewicz
Dianna
D
Tilton
Ronald G
RG
Brasier
Allan R
AR
D019264:Adoptive Transfer; D000784:Aortic Dissection / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001014:Aortic Aneurysm / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D018920:Coculture Techniques; D003238:Connective Tissue / Q000473:pathology / Q000503:physiopathology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D017931:DNA Primers; D015850:Interleukin-6; D054390:Receptors, CCR2; D000804:Angiotensin II