MicroRNA‐146 represses endothelial activation by inhibiting pro‐inflammatory pathways

Abstract

Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.

In vitro screening of LPS-induced miRNAs in leukocytes derived from cord blood and their possible roles in regulating TLR signals

“…In addition, activation of the MAP kinase/EGR pathway by proinflammatory cytokines regulates the transcription of the miR-146, which can in turn repress the NF-κB, AP-1, and MAPK/EGR pathways. Thus, a negative feedback loop is formed to control the proinflammatory signaling in endothelial cells that may impact the pathogenesis of vascular inflammatory diseases such as sepsis (27). In our study, the expression of miR-146b was upregulated in CB leukocytes after LPS stimulation, indicating that miR-146b might have an important role in controlling LPSstimulated neonatal early phases of inflammation by engaging in negative feedback loops.…”

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

“…RNA was extracted and cDNA was amplified and normalized by geometric averaging of glyceraldehyde 3-phosphate dehydrogenase, hypoxanthine-guanine phosphoribosyltransferase and 18S expression levels as described (24). miR-155 relative expression was normalized to U6 as described (25). The primer sequences used (5′-3′) are shown in Supplementary Table S1.…”

Apolipoprotein E Epsilon 4 Enhances the Association between the rs2910164 Polymorphism of miR-146a and Risk of Atherosclerotic Cerebral Infarction

“…MiR-146a is assumed to be protective against atherosclerosis given its ability to suppress NF-B signaling, the TLR4 signaling pathway, and the apparent activation of endothelial cells. miR-146a levels were elevated in human atherosclerotic plaques as well as in the circulation and plaques of atherosclerotic mice because of the strong activation of NF-B signaling in plaques, implying that miR-146a is induced as part of a negative feedback loop 32,39,40) . Xiong et al stated that the GC and CC genotypes of the miRNA-146a rs2910164 polymorphism are associated with an increased risk of CAD 41) , whose risk subsequently increases with the presence of metabolic increasing the risk of ACI 46) .…”