A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons

Abstract

Background: Toll like receptors (TLR) play an important role in vein graft disease (VGD). Interferon regulatory factors (IRF) 3 and 7 are the transcriptional regulators of type I interferons (IFN) and type I IFN responsive genes and are downstream factors of TLRs. Relatively little is known with regard to the interplay of IRFs and TLRs in VGD development. The aim of this study was to investigate the role of IRF3 and IRF7 signaling downstream TLRs and the effect of IRF3 and IRF7 in VGD. Methods and Results: In vitro activation of TLR3 induced IRF3 and IRF7 dependent IFNβ expression in bone marrow macrophages and vascular smooth muscle cells. Activation of TLR4 showed to regulate pro-inflammatory cytokines via IRF3. Vein graft surgery was performed in Irf3−/−, Irf7−/− and control mice. After 14 days Irf3−/− vein grafts had an increased vessel wall thickness compared to both control (P = 0.01) and Irf7−/− (P = 0.02) vein grafts. After 28 days, vessel wall thickness increased in Irf3−/− (P = 0.0003) and Irf7−/− (P = 0.04) compared to control vein grafts and also increased in Irf7−/− compared to Irf3−/− vein grafts (P = 0.02). Immunohistochemical analysis showed a significant higher influx of macrophages after 14 days in Irf3−/− vein grafts and after 28 days in Irf7−/− vein grafts compared to control vein grafts. Conclusions: The present study is the first to describe a protective role of both IRF3 and IRF7 in VGD. IRFs regulate VGD downstream TLRs since Irf3−/− and Irf7−/− vein grafts show increased vessel wall thickening after respectively 14 and 28 days after surgery.