Abstract 5164: Loss of SOCS3 Expression in T Cells Reveals a Regulatory Role for Interleukin-17 in Atherosclerosis

Abstract

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immuno-inflammatory balance in the modulation of disease development and progression. However, the immuno-regulatory pathways that control atherosclerosis remain largely unknown. Here, we show that loss of Suppressor of Cytokine Signaling 3 (SOCS3) in T cells increases both interleukin (IL)17 and IL10 production, induces an anti-inflammatory macrophage phenotype, and leads to unexpected IL17-dependent reduction in lesion development and vascular inflammation. In vivo administration of IL17 reduces endothelial vascular cell adhesion molecule (VCAM)-1 expression, vascular T cell infiltration and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of Stat3 phosphorylation and IL17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL17 regulatory pathways in atherosclerosis and may have important implications to the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 differentiation.