Date of Award

Summer 8-18-2023

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Sergey Ryzhov

Second Committee Member

Igor Prudovsky

Third Committee Member

Robert Friesel

Additional Committee Members

Calvin Vary

Pradeep Sathyanarayana

Robert Gundersen

Abstract

The Interleukin-17 (IL17) family is a group of cytokines implicated in the etiology of several inflammatory diseases. Interleukin-17 receptor D (IL17RD), also known as Sef (similar expression to fibroblast growth factor), belonging to the family of IL17 receptors, has been shown to modulate IL17A-associated inflammatory phenotypes. The objective of this study was to test the hypothesis that IL17RD promotes endothelial cell activation and consequent monocyte adhesion. We utilized primary human aortic endothelial cells and demonstrated that RNAi targeting of IL17RD suppressed transcript levels by 83% compared to non-targeted controls. Further, RNAi knockdown of IL17RD decreased the adhesion of THP-1 cells onto a monolayer of aortic endothelial cells in response to IL17A. Additionally, we determined that IL17A did not significantly enhance the activation of canonical MAPK and NFκB pathways in endothelial cells and further did not significantly affect the expression of VCAM-1 and ICAM-1 in aortic endothelial cells, which is contrary to previous findings. We also determined the functional relevance of our findings in vivo by comparing the expression of VCAM-1 and ICAM-1 and leukocyte infiltration in the aorta in Western diet-fed Il17rd null versus wild-type mice. Our results showed that although Il17rd null mice do not have significant alteration in aortic expression of VCAM-1 and ICAM-1 in endothelial cells, they exhibit a decreased accumulation of proinflammatory monocytes and neutrophils, suggesting that endothelial IL17RD enhances myeloid cell accumulation in a CAM-independent manner in vivo. We further assessed the pathophysiological relevance of our findings by initiating atherogenesis in global and endothelial cell-specific Il17rd loss of function mouse models using an AAV-mPCSK9 approach. Our results suggest that although endothelial Il17rd does not affect the aortic lesion area, Il17rd modulates circulating levels of IL23 and IL27. Collectively, our results underscore a critical role for Il17rd in the regulation of WD-induced myeloid cell infiltration and proinflammatory cytokines in vivo.

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