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A protective role of IRF 3 and IRF 7 signalling downstream TLR s in the development of vein graft disease via type I interferons
Author(s) -
Simons K. H.,
Peters H. A. B.,
Jukema J. W.,
Vries M. R.,
Quax P. H. A.
Publication year - 2017
Publication title -
journal of internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.625
H-Index - 160
eISSN - 1365-2796
pISSN - 0954-6820
DOI - 10.1111/joim.12679
Subject(s) - irf3 , irf7 , interferon regulatory factors , microbiology and biotechnology , immunology , biology , innate immune system , immune system
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 TLR s. Relatively little is known with regard to the interplay of IRF s and TLR s in VGD development. The aim of this study was to investigate the role of IRF 3 and IRF 7 signaling downstream TLR s and the effect of IRF 3 and IRF 7 in VGD . Methods and Results In vitro activation of TLR 3 induced IRF 3 and IRF 7 dependent IFN β expression in bone marrow macrophages and vascular smooth muscle cells. Activation of TLR 4 showed to regulate pro‐inflammatory cytokines via IRF 3. 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 Irf 7 −/− ( 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 IRF 3 and IRF 7 in VGD . IRF s regulate VGD downstream TLR s since Irf3 −/− and Irf7 −/− vein grafts show increased vessel wall thickening after respectively 14 and 28 days after surgery.