Double ‐ Stranded RNA Analog Poly I:C Enhances the Expression of Lectin‐Like Oxidized LDL Receptor‐1 in Macrophages: Role of ERK1/2 Signaling

Abstract

We previously reported that bacterial lipopolysaccharide (LPS) enhanced the expression of lectin-like oxidized LDL receptor-1 (LOX-1) in macrophages through activation of the ERK1/2 signaling, thereby enhancing the cellular uptake of ox-LDL. Polyinosinic:polycytidylic acid (Poly I:C), a synthetic analog of double-stranded RNA (dsRNA), which activates various cell signaling via TLR3, has been shown to accelerate atherosclerotic lesions in multiple animal models. However, the underlying molecular mechanism mediating this response is obscure. Therefore, the present study aimed to investigate whether or not Poly I:C affects the expression of LOX-1 and explore the underlying molecular mechanisms. In RAW 264.7 macrophages, Poly I: C stimulation dose- and time-dependently enhanced the expression of LOX1. Although Poly I:C induced the activation of MAP kinases (p38, JNK1/2, ERK1/2), AP1 (c-FOS/JUN), and NF-kB signaling molecules, a specific ERK1/2 inhibitor (U0128) effectively inhibited the upregulation of LOX-1. Additionally, transient knockdown of ERK1/2 by small interference RNA prevented Poly I:C-induced overexpression of LOX1. Poly I:C stimulation augmented LOX-1 promoter activity, which is also inhibited by U0126 treatment. Similar results were also observed in human PMA-induced THP-1 human macrophages. Overall, we sought that Poly I:C, a viral mimic, upregulates the expression of LOX-1 through activation of the ERK1/2 signaling, highlighting a critical role of TLR3-mediated impaired LOX-1 signaling in the pathogenesis of atherosclerosis.