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

Xiaoxi Ju, Talha Ijaz, Hong Sun, Sutapa Ray, Wanda Lejeune, Chang Lee, Adrian Recinos, Dong Chuan Guo, Dianna M. Milewicz, Ronald G. Tilton, Allan R. Brasier

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1612-1621
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number7
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Angiotensin II
  • Aortic dissection
  • Familial
  • Helper
  • Inflammation
  • Interleukin-6
  • T-lymphocytes
  • Vascular inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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