The Role of IL-6 in Inflammatory Aortic Aneurysmal Diseases

Interleukin-6 (IL-6), a member of a superfamily of cardioactive cytokines, has been identified as an independent biomarker of vascular diseases including atherosclerosis and aortic aneurysms. Local vascular IL-6 secretion can be induced by dysregulated angiotensin II (Ang II) signaling, producing leukocyte infiltration that results in life-threatening aortic aneurysms and dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. In this study, we employed two experimental animal models to study the role of IL-6 activation in the development and progression of aortic aneurysms. In an Ang II-treated C57BL/6 mice model, we tested the relationship of IL-6 signaling with Th17-induced inflammation in the formation of Ang II-induced aortic dissections. We found that Ang II infusion induced aortic dissections and CD4+-interleukin 17A (IL-17A)-expressing, Th17 cell accumulation in C57BL/6 mice. IL-6-deficient mice showed blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections, suggesting the importance of IL-6 signaling in inducing Th17-mediated aneurysmal progression. We further showed the pathological roles of Th17 lymphocytes by depleting Th17 by IL-17A neutralization or genetic mutation and showed decreased aortic chemokine MCP-1 production and macrophage recruitment, leading to a reduction in aortic dissections. We also established clinical relevance by showing increased Th17 infiltration into the aortic adventitial-medial border in patients with ascending aortic dissections. These findings indicate that IL-6 signaling converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating vascular inflammation and aortic dissections. In another mouse model with spontaneous aortic aneurysms due to Marfan Syndrome (MFS) caused by Fbn-1 gene mutation (mgR homozygotes), we also reported elevated IL-6 signaling and increased macrophage recruitment in ascending aneurysmal tissues. To study the role of IL-6 signaling, we generated mgR homozygotes with IL-6 deficiency (DKOs), which showed reduction in aneurysmal dilation at late stage of disease with unaffected survival rate. Moreover, we reported that IL-6 deficiency led to decreased ECM degradation that is associated with reduced levels of local MMPs. These findings suggests the activation of IL-6-mediated inflammatory signaling contributed to aneurysmal progression in MFS through recruitment of leukocytes and stimulation of MMP expression, thus aggravating ECM degradation and vascular remodeling.

Name thesis:degree_name

Biochemistry and Molecular Biology (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Cell Biology and Molecular Biology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Ju, Xiaoxi 1984-

Advisor dc:contributor.advisor

• Fujise, Ken

Committee members dc:contributor.committeemember

• Brasier, Allan R
• Tilton, Ronald G
• Milewicz, Dianna M
• Vargas, Gracie
• Wakamiya, Maki

• Interleukin-6
• Aortic aneurysms
• Aortic dissections
• Angiotensin II
• Th17
• marfan syndrome

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/828

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/828