Type I Interferons and the Development of Impaired Vascular Function and Repair in Human and Murine Lupus.

Abstract

Patients with systemic lupus erythematosus (SLE), an autoimmune disease of unclear etiology, have a greatly increased risk of developing premature atherosclerotic cardiovascular disease (CVD), independent of traditional vascular risk factors. While CVD is a major cause of mortality and morbidity in these patients, the exact mechanisms behind this increased vascular risk are unknown. SLE patients develop a profound imbalance of vascular damage and repair which is mediated by interferon (IFN)-α and, potentially, by other type I IFNs. This dissertation elucidates the molecular mechanisms by which IFN-α inhibits vascular repair mediated by endothelial progenitor cells (EPCs), and demonstrates that type I IFNs play a key role in the development of endothelial dysfunction in lupus-prone and non-lupus-prone mice in vivo. Using a gene expression array approach, we identified that IFN-α promotes antiangiogenic responses in EPCs through repression of IL-1 signaling and of vascular endothelial growth factor. These effects are mediated through the JAK/STAT pathway. These transcriptional abnormalities are operational in vivo, as evidenced by vascular rarefaction observed in human lupus tissues. In murine studies, we identified that the lupus prone mouse strain New Zealand Black/New Zealand White F1 displays an abnormal vascular phenotype similar to human SLE. In the closely related NZM 2328 strain, we demonstrate that type I IFNs induce endothelial dysfunction, decreased neoangiogenesis and enhanced platelet activation. These deleterious effects on the vasculature mediated by type I IFNs were not secondary to lupus disease activity, gender or lupus prone phenotype. Furthermore, type I IFNs are also involved in atherosclerosis severity and acceleration of thrombosis in Apolipoprotein-E deficient mice, an atherosclerosis-prone mouse strain. Our results strongly suggest that type I IFNs play a vital role in the induction of endothelial dysfunction and aberrant vascular repair in lupus through the inhibition of important proangiogenic molecules. These results also indicate that type I IFNs may play a deleterious role in the vasculature in “idiopathic” atherosclerosis not related to systemic autoimmune diseases. These observations could also have important implications in the identification of therapeutic targets to prevent CVD and in the understanding on how microbial infections may trigger vascular damage.