Abstract 510: Type I Interferons Promote Atherosclerosis By Affecting Chemotaxis And Cell Death
Type I interferons (IFN-Is) belong to a family of cytokines well known to mediate antiviral responses but also both pro- and anti-inflammatory immune cell functions. Clinically, they are used as antiviral and antitumour drugs and in the treatment of relapsing remitting multiple sclerosis. Since atherosclerosis is an inflammatory disease in which the regulation of immune cells highly determines disease severity, we investigated the role of IFN-Is in atherosclerotic plaque development. Increased collar-induced atherosclerotic lesion formation, with lesions mainly composed of macrophages, was observed in daily IFNβ (5000U) treated apoe−/− mice on a high fat diet. IFNβ induced expression of both the chemokine RANTES (160-fold) and its receptor CCR5 (3.5-fold) in primary macrophages in vitro, while surface expression of integrins was unaltered. Subsequently, IFNβ was shown to enhance in vitro static adhesion of macrophages to endothelial cells by 65%. Moreover, IFNβ increased monocyte arrest at atherosclerotic sites by (12 ± 4 vs 38 ± 6 cells/HPF) as assessed using intravital microscopy in IFNβ treated apoe−/− mice. This effect appeared to be RANTES-dependent since it could be abrogated by co-treatment of the animals with Met-RANTES (10 ± 1 cells/HPF). To study a potential role of endogenous IFN-I signaling in atherosclerosis we transplanted bone marrow cells from mice lacking the IFN receptor, IFNAR1, specifically in their myeloid lineage to ldlr−/− mice and fed them a high fat diet. Deletion of IFNAR1 in myeloid cells led to a 34% reduction in lesion development with less accumulation of macrophages (−22%) and neutrophils (−54%) in the plaques. Moreover, the lesions showed a more stable plaque phenotype characterized by a 71% reduced necrotic core formation. In vitro studies showed that IFNAR1 is necessary for the induction of CCR5 and RANTES by either IFN-I or LPS. Collectively, these data show that IFN-I signaling enhances atherogenesis by promoting the attraction of immune cells to atherosclerotic lesions and that it influences plaque stability by affecting lesional necrotic core formation. Hereby, we identify IFN-Is as novel players in atherosclerosis development and plaque stability.