How does interferon‐α insult the vasculature? Let me count the ways

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). The basis for decreased vascular repair and the antiangiogenic signature in EPCs and CACs induced by IFN-α appears to be repression of interleukin-1 (IL-1) pathways, upregulation of the IL-1 receptor antagonist (IL-1RN) and downregulation of the proangiogenic molecule vascular endothelial growth factor (VEGF)(4). Such an antiangiogenic pathway is present in vivo in SLE patients who demonstrate vascular rarefaction, repression of VEGF and increases in IL-1RN in lupus renal blood vessels and serum (4). Although it is possible that decreased IL-1 and increased IL-1RN represents a phenotype that protects the vasculature, a cytokine profile that enhances antiangiogenic responses might also be considered to be vasculopathic and accelerate atherosclerosis in SLE. Indeed, vascular insults in SLE, in conjunction with increased levels of type I IFNs, may lead to periods of endothelial damage, followed by aberrant repair due to decreased IL-1 and VEGF-A and increased IL-1RN. Such cyclic injury and failed repair would allow initiation and expansion of vascular lesions during these flares (4). Recent evidence indicates that IFN-α may additionally contribute to the development of acute vascular events through an effect on platelet function(11). Gene array expression studies on lupus platelets revealed increased expression of type I IFN-regulated genes confirmed at the protein level which is paired to increased platelet activation. Indeed, platelets from SLE patients with a history of vascular disease have increased levels of type I IFN-regulated proteins and increased activation when compared to those from SLE patients without vascular disease history (11). Conversely, lupus platelets activated by circulating immune complexes form aggregates with antigen-presenting cells, such as monocytes and plasmacytoid dendritic cells (pDCs), leading to enhancement of IFN-α secretion through CD154-CD40 interactions (12). A feed-forward loop then develops, wherein type I IFNs induce platelet activation which triggers platelet to synthesize IFN-α and, potentially, leads to increased thrombotic risk. Although the IFN-α link with abnormal vascular repair and enhanced potential for vascular injury has been firmly established, the transformation of recruited monocytes into lipid-laden macrophages, or ‘foam cells’, central to the development of atherosclerotic lesions (13), was not known to be related to IFN-α. The scavenger receptors SR-A and CD36 have been implicated in foam cell formation and in the regulation of inflammatory signaling pathways leading to lesional macrophage apoptosis and plaque necrosis (14). In this issue of Arthritis & Rheumatism, Li et al provide key evidence that IFN-α plays a direct role in the development of accelerated atherosclerosis in SLE. They report that IFN-α priming increases the uptake of oxidized-low density lipoprotein (ox-LDL) by macrophages, thereby enhancing foam cell formation. Enhanced ox-LDL uptake by IFN is induced by the selective upregulation of the SR-A through an effect on its promoter activity, which requires phosphatidylinositol 3-kinase (PI3K)-Akt pathways. They provide evidence that this phenomenon is operational in vivo in patients, as SR-A mRNA was increased in SLE PBMCs compared to healthy controls, and positively correlated with levels of type I IFN inducible genes. Importantly, levels of SR-A in mononuclear cells have been linked to acute coronary events in other patient populations (15). It is important to note that the diverse deleterious effects of type I IFNs on the vasculature may apply not only to lupus. Indeed, recent evidence indicates a role for type I IFNs in the pathogenesis of other autoimmune conditions, including Sjogren’s syndrome, psoriasis, inflammatory myopathies and progressive systemic sclerosis. As vascular damage is also accelerated in these diseases, it would be important to assess the prevalence and correlates of atherosclerosis in these disease populations and the contribution of type I IFNs to this complication. Further, studies in atherosclerotic arteries from individuals without systemic autoimmune diseases demonstrate that plaque-residing pDCs produce excess IFN-α which sensitizes antigen-presenting cells toward pathogen-derived Toll-like receptor 4 ligands. Thus, local production of IFN-α leads to enhanced synthesis of the proinflammatory cytokines and matrix metalloproteinases implicated in atherosclerotic plaque destabilization. IFN-α expressed within the plaque stimulates cytotoxic T-cells in blood vessels augmenting vascular damage. These studies indicate that pathogens or nucleosome-containing immune complexes, that induce synthesis of IFN-α m a y threaten the stability of inflamed atherosclerotic plaques (16, 17). Identifying a newly described role for type I IFNs as enhancers of foam cell formation expands that pleiotropic effects of this cytokine on the vasculature from early endothelial cell damage and dysregulated repair of the damaged vasculature, to the development of atherosclerotic plaque, its destabilization and the development of acute coronary syndromes through thrombosis enhancement. With expanded understanding of the IFN pathway in SLE, identification of associations between type I IFNs, endothelial dysfunction and atherosclerosis in lupus, and development of new biologics that block IFN-α currently in preclinical and clinical trials (18, 19), we are poised perform studies to address causality of IFN-α and development of atherosclerosis in this disease. Given compelling evidence that IFN-α is an appropriate target to modulate CV risk in SLE, it is the responsibility of investigators and industry-partners who design lupus trials with inhibitors of IFN-α, to include biomarkers of vascular damage and functional studies of vascular health as endpoints in their efficacy analysis. This should be the case not only in SLE, but also in other autoimmune diseases where anti-IFN-α therapies are currently being tested. It is the hope that these drugs may translate into improved patient care in SLE not only through abrogation of disease activity but, also, through the decrease of end-organ damage and fatal vascular complications that afflict so many individuals with this disease.