Abstract 507: Adipocyte-specific Cytokine Signaling Regulates Inflammation And Atherosclerosis

Abstract

Adipose tissue inflammation has been implicated in various chronic inflammatory diseases and cancer. Perivascular adipose tissue (PVAT) surrounds the aorta as a fourth layer and was previously shown to regulate the function of endothelial and vascular smooth muscle cells. Moreover, PVAT contains various immune cells and therefore could contribute to the inflammatory environment in the aorta during atherosclerosis development via cross-talk with adventitia. We found that Western diet (WD) feeding increases the accumulation of immune cells in PVAT of atherosclerosis-prone Ldlr -/- mice and increases the expression of IL-1β. As IL-1 is essential for atherosclerosis development and its inhibition in patients in CANTOS trial reduced inflammation and cardiovascular events, we further evaluated the potential role of IL1R signaling in adipocytes of PVAT.We found that adipocyte-specific ablation of IL1R in Il1r fl/fl Ldlr -/- AdipoCre + mice fed with Western Diet for 16 weeks led to significant reduction in atherosclerosis when compared to Il1r fl/fl Ldlr -/- AdipoCre - controls. Gene expression analysis of isolated adipocytes revealed a significant reduction of expression of several chemokines, including Ccl2, Ccl5, Ccl7 as well as pro-atherogenic cytokines IL-6 and IL-1β . The analysis of immune cell composition by Flow cytometry and scRNA sequencing further demonstrated reduced representation of key pro-inflammatory cell subsets in PVAT of l1r fl/fl Ldlr -/- AdipoCre + which also reflected in their reduced accumulation in the aorta and atherosclerotic plaques. Our data suggest novel adipocyte-specific mechanisms controlling inflammation in atherosclerosis. IL1R signaling therefore directly regulates pro-inflammatory chemokines and cytokines in adipocytes thereby controlling immune cell recruitment to PVAT and aortic wall, which in turn contributes to the enhanced aortic inflammation and atherosclerosis.