MicroRNA-155 Silencing Enhances Inflammatory Response and Lipid Uptake in Oxidized Low-Density Lipoprotein-Stimulated Human THP-1 Macrophages

Abstract

It has been proposed that the inflammatory response of monocytes/macrophages induced by oxidized low-density lipoprotein (oxLDL) is a key event in the pathogenesis of atherosclerosis. MicroRNA-155 (miR-155) is an important regulator of the immune system and has been shown to be involved in acute inflammatory response. However, the function of miR-155 in oxLDL-stimulated inflammation and atherosclerosis remains unclear. Here, we show that the exposure of human THP-1 macrophages to oxLDL led to a marked up-regulation of miR-155 in a dose-dependent manner. Silencing of endogenous miR-155 in THP-1 cells using locked nucleic acid-modified antisense oligonucleotides significantly enhanced oxLDL-induced lipid uptake, up-regulated the expression of scavenger receptors (lectinlike oxidized LDL receptor-1, cluster of differentiation 36 [CD36], and CD68), and promoted the release of several cytokines including interleukin (IL)-6, -8, and tumor necrosis factor α (TNF-α). Luciferase reporter assay showed that targeting miR-155 promoted nuclear factor-kappa B (NF-κB) nuclear translocation and potentiated the NF-κB-driven transcription activity. Moreover, miR-155 knockdown resulted in a marked increase in the protein amount of myeloid differentiation primary response gene 88 (MyD88), an important adapter protein used by Toll-like receptors to activate the NF-κB pathway. Our data demonstrate that miR-155 serves as a negative feedback regulator in oxLDL-stimulated THP-1 inflammatory responses and lipid uptake and thus might have potential therapeutic implications in atherosclerosis.

The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome

“…13 miR-155 is upregulated in activated immune cells 17 and modulates immune responses by regulating cell differentiation (such as Th1 and Treg) and cytokine secretion (such as tumor necrosis factor-alpha) and IL-6). [18][19][20] However, we found that miR-155 was downregulated in patients with ACS, which was consistent with what Fichtlscherer et al 21 found in patients with coronary artery disease. Two mechanisms may explain these findings.…”

MicroRNAs in the Atherosclerotic Plaque

“…When the differentiated macrophages are treated with oxLDL to stimulate foam cell formation, miR-146a, -146b-5p, -155, -9, and -125a-5p expressions are upregulated (61 ). Of these upregulated miRNAs, miR-155 functions as a negative feedback regulator, decreasing the inflammatory response and lipid uptake through scavenger receptors (62 ). In contrast to Chen et al (62 ), Yang et al found miR-146a to be significantly downregulated in oxLDLstimulated macrophages.…”

“…Of these upregulated miRNAs, miR-155 functions as a negative feedback regulator, decreasing the inflammatory response and lipid uptake through scavenger receptors (62 ). In contrast to Chen et al (62 ), Yang et al found miR-146a to be significantly downregulated in oxLDLstimulated macrophages. They also found this miRNA to have very similar functions as miR-155 after the stimulation, mainly decreasing cytokine production and lipid uptake (63 ).…”

Negative feedback regulation between microRNA let-7g and the oxLDL receptor LOX-1

“…The let-7 family plays a pivotal role in cell proliferation (Lan et al, 2011), cancer (Bussing et al, 2008;Schultz et al, 2008) and cardiovascular diseases (Zhang, 2008). Several studies have reported that LOX-1 activation could enhance downstream gene regulation including miRNAs (Li and Mehta, 2009;Huang et al, 2010). The LOX-1 39-untranslated region (UTR) was predicted, using bioinformatic tools RNA22 (Miranda et al, 2006) and Targetscan (Friedman et al, 2009), to have a putative target site for let-7g.…”