Interleukin-6–Signal Transducer and Activator of Transcription-3 Signaling Mediates Aortic Dissections Induced by Angiotensin II via the T-Helper Lymphocyte 17–Interleukin 17 Axis in C57BL/6 Mice

Abstract

Objective— Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6–signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II–induced dissections in C57BL/6 mice. Approach and Results— Ang II infusion induced aortic dissections and CD4 + -interleukin 17A (IL-17A)–expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6 −/− mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II–infused mice with IL-17A–neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A–neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II–mediated aortic dissections occurred independent of blood pressure changes. Conclusions— Our results indicate that the IL-6–signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.