The IL-17A/IL-17RA Axis Plays a Proatherogenic Role via the Regulation of Aortic Myeloid Cell Recruitment

Abstract

Rationale: Atherosclerosis is a disease of large- and medium-sized arteries that is characterized by chronic vascular inflammation. While the role of Th1, Th2, and T-regulatory subsets in atherogenesis is established, the involvement of IL-17A-producing cells remains unclear. Objective: To investigate the role of the IL-17A/IL-17RA axis in atherosclerosis. Methods and Results: We bred apolipoprotein-E-deficient ( Apoe −/− ) mice with IL-17A-deficient and IL-17 receptor A-deficient mice to generate Il17a −/− Apoe −/− and Il17ra −/− Apoe −/− mice. Western diet fed Il17a −/− Apoe −/− and Il17ra −/− Apoe −/− mice had smaller atherosclerotic plaques in the aortic arch and aortic roots, but showed little difference in plaque burden in the thoracoabdominal aorta in comparison with Apoe −/− controls. Flow cytometric analysis of Il17a −/− Apoe −/− and Il17ra −/− Apoe −/− aortas revealed that deficiency of IL-17A/IL-17RA preferentially reduced aortic arch, but not thoracoabdominal aortic T cell, neutrophil, and macrophage content in comparison with Apoe −/− aortic segments. In contrast to ubiquitous IL-17RA expression throughout the aorta, IL-17A was preferentially expressed within the aortic arch of WD-fed Apoe −/− mice. Deficiency of IL-17A or IL-17RA reduced aortic arch, but not thoracoabdominal aortic TNFα and CXCL2 expression. Aortic vascular IL-17RA supports monocyte adherence to explanted aortas in ex vivo adhesion assays. Short-term homing experiments revealed that the recruitment of adoptively transferred monocytes and neutrophils to the aortas of Il17ra −/− Apoe −/− mice is impaired in comparison with Apoe −/− recipients. Conclusions: The IL-17A/IL-17RA axis increases aortic arch inflammation during atherogenesis through the induction of aortic chemokines, and the acceleration of neutrophil and monocyte recruitment to this site.