Systemic lupus erythematosus (SLE) is associated with a very significant increase in atherosclerotic cardiovascular (CV) complications (1), not explained by traditional risk factors (2). While corticosteroids and cytotoxic agents can effectively manage and control various lupus-related complications, no drug to this date has proven to prevent the development of premature atherosclerosis in SLE. As such, establishing the key drivers of vascular insult and atherosclerosis progression in lupus is a priority to identify therapeutic targets that could play an important role in the prevention of CV damage in this disease.

While the etiology of premature vascular damage in lupus remains unclear and is likely multifactorial, recent evidence indicates that type I Interferons (IFNs) could play a prominent role in endothelial cell damage and by extension could contribute to the development of atherosclerosis in SLE (3, 4). Accumulating evidence from multiple research groups supports a broad activation of the type I IFN pathway in lupus associated with clinical manifestations and disease activity and suggest that this pathway plays an important role in disease pathogenesis (5, 6). More recently, a link between type I IFNs, vascular damage and progression of atherosclerosis in SLE has emerged. Patients with SLE develop a profound imbalance between endothelial cell damage and repair. This imbalance is characterized by accelerated endothelial cell apoptosis (7) and aberrant phenotype and function of cells critical to vasculogenesis: bone marrow-derived endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs)(3, 8, 9). The alteration in EPC/CAC phenotype and function in SLE patients and some lupus animal models is profound (3, 10), and comparable to that observed in patients with diabetes mellitus, the prototype condition characterized by aberrant vasculogenesis. That type I IFNs play a prominent role in the induction of decreased vascular repair is indicated by the observations that abrogation of type I IFN signaling in lupus EPCs/CACs leads to restoration of a normal phenotype and EPCs/CACs isolated from healthy controls and exposed to IFN-α, develop the phenotypic and functional characteristics of lupus cells (3). Furthermore, high IFN-I levels are associated with impaired endothelial function in patients with SLE (8).