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

42 Citations (Scopus)

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
Externally publishedYes

Fingerprint

STAT3 Transcription Factor
Interleukin-17
Angiotensins
Inbred C57BL Mouse
Dissection
Interleukin-6
Lymphocytes
Angiotensin II
Helper-Inducer T-Lymphocytes
Th17 Cells
Macrophages
Neutralizing Antibodies
Blood Vessels
Leukocytes
Blood Pressure
Lymphocyte Activation
Chemokines
Dilatation
Thorax
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 33, No. 7, 01.07.2013, p. 1612-1621.

Research output: Contribution to journalArticle

Ju, Xiaoxi ; Ijaz, Talha ; Sun, Hong ; Ray, Sutapa ; Lejeune, Wanda ; Lee, Chang ; Recinos, Adrian ; Guo, Dong Chuan ; Milewicz, Dianna M. ; Tilton, Ronald G. ; Brasier, Allan R. / 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. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2013 ; Vol. 33, No. 7. pp. 1612-1621.
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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.",
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AU - Ijaz, Talha

AU - Sun, Hong

AU - Ray, Sutapa

AU - Lejeune, Wanda

AU - Lee, Chang

AU - Recinos, Adrian

AU - Guo, Dong Chuan

AU - Milewicz, Dianna M.

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