Ablation of Interferon Regulatory Factor 3 Protects Against Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

The secretion of adhesion molecules by endothelial cells, as well as the subsequent infiltration of macrophages, determines the initiation and progression of atherosclerosis. Accumulating evidence suggests that IRF3 (interferon regulatory factor 3) is required for the induction of proinflammatory cytokines and for endothelial cell proliferation. However, the effect and underlying mechanism of IRF3 on atherogenesis remain unknown. Our results demonstrated a moderate-to-strong immunoreactivity effect associated with IRF3 in the endothelium and macrophages of the atherosclerotic plaques in patients with coronary heart disease and in hyperlipidemic mice. IRF3 − / − ApoE −/− mice showed significantly decreased atherosclerotic lesions in the whole aorta, aortic sinus, and brachiocephalic arteries. The bone marrow transplantation further suggested that the amelioration of atherosclerosis might be attributed to the effects of IRF3 deficiency mainly in endothelial cells, as well as in macrophages. The enhanced stability of atherosclerotic plaques in IRF3 −/− ApoE −/− mice was characterized by the reduction of necrotic core size, macrophage infiltration, and lipids, which was accompanied by increased collagen and smooth muscle cell content. Furthermore, multiple proinflammatory cytokines showed a marked decrease in IRF3 −/− ApoE −/− mice. Mechanistically, IRF3 deficiency suppresses the secretion of VCAM-1 (vascular cell adhesion molecule 1) and the expression of ICAM-1 (intercellular adhesion molecule 1) by directly binding to the ICAM-1 promoter, which subsequently attenuates macrophage infiltration. Thus, our study suggests that IRF3 might be a potential target for the treatment of atherosclerosis development.

Ablation of Interferon Regulatory Factor 3 Promotes the Stability of Atherosclerotic Plaques

“…Utilizing chromatin immunoprecipitation (Chip) assay in HUVECs, followed by PCR of ICAM-1 and VCAM-1 promoters, a specific and direct binding of IRF3 to region P1 of ICAM promoter was confirmed. 5 Depletion of IRF3 using specific siRNA in HUVECs and subsequent treatment with TNF-α, correlated with significant decrease in ICAM-1 and VCAM-1 expression at both the mRNA and protein levels. 5 Together, these findings highlight an established network of inflammatory trigger on endothelial integrity, and subsequent pro-atherogenic events via altered secretion of adhesion molecules.…”

“…In response to stimuli, IRF3 may become activated via phosphorylation, and translocate into the nucleus. 5 In this study, the authors observed that IRF3 was increased in patients with coronary heart disease (CHD). Upregulated IRF3 level was confirmed further using ApoE-deficient mice, a commonly used atherosclerotic mice model relative to IRF3 −/− ApoE −/− .…”

“…5 IRF3 is a member of the interferon regulatory factor family which comprises of transcriptional regulators of the interferon (IFN)-induced signaling pathway. 5 Mammalian IRF consists of 9 members that possess various biological functions, and IRF3 is somewhat unique in that inactive forms are predominantly localized in the cytosol. In response to stimuli, IRF3 may become activated via phosphorylation, and translocate into the nucleus.…”

“…It was further observed that hyperlipidimic IRF3 −/− ApoE −/− mice were resistant to high-fat diet-induced atherogenesis, while displaying decreased plaque inflammation and improved plaque stability. 5 Another highpoint of the article was the observation that several defining hallmarks of stable plaques, including thick fibrous cap cover, increased collagen deposition and smooth muscle cell (SMC) content, as well as decreased macrophage infiltration were evident upon ablation of IRF3 expression. 5,6 Cross-group bone marrow transplantation demonstrated that IRF3 deficiency in endothelial cells was critical for decreased plaque development rather than bone marrow-derived macrophages.…”

“…5,6 Cross-group bone marrow transplantation demonstrated that IRF3 deficiency in endothelial cells was critical for decreased plaque development rather than bone marrow-derived macrophages. 5 …”