LPS induces CXCL16 expression in HUVECs through the miR-146a-mediated TLR4 pathway

Xiao, Qi; Zhu, Xiaoyan; Yang, Shaonan; Wang, Jing; Yin, Ruihua; Song, Jinyang; Ma, Aijun; Pan, Xudong

doi:10.1016/j.intimp.2019.01.011

Cited by 31 publications

(14 citation statements)

References 25 publications

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“…The mechanism is associated with the decreased recruitment of macrophages, which occurs by reducing the adhesion molecules and pro-inflammatory cytokine expression (32,34). MiR-146a has been shown to inhibit NF-κB phosphorylation to negatively regulate LPS-induced inflammatory cytokine production in ECs (35). Similarly, we found miR-146a-5p overexpression repressed the level of phospho-NF-κB in HUVECs, resulting in a significant decrease in pro-inflammatory cytokine expression and secretion.…”

Section: Discussionmentioning

confidence: 52%

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Hou¹,

Deng²,

Deng

et al. 2021

Ann Transl Med

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Background: Microribonucleic acids (miRNAs) have an evident role in regulating endothelial inflammation and dysfunction, which characterizes the early stages of atherosclerosis. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to contribute to the endothelial inflammatory response that promotes atherosclerosis development and progression.This study sought to investigate the effects of miR-146a-5p on lipopolysaccharide (LPS)-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production in human umbilical vein endothelial cells (HUVECs).Methods: HUVECs were transfected with a miR-146a-5p mimic, small-interfering RNA (siRNA) (si-TRAF6, and si-IRAK1), and were then stimulated with LPS for 24 h. The messenger (mRNA) and the protein levels of p-NF-κB/NF-κB, NLRP3, Caspase-1, pro-inflammatory cytokine [interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α)] in the HUVECs were analyzed by quantitative real-time polymerase chain reactions (PCRs) and western blot assays, respectively. The secretion of IL-6 from the cells was detected by enzyme-linked immunoassay (ELISA). Bioinformatic and dual-luciferase reporter assays were performed to identify the targets of miR-146a-5p.Results: LPS promoted pro-inflammatory cytokine expression in a dose-dependent manner and significantly increased the expression levels of p-NF-κB/NF-κB p65, NLRP3, and Caspase-1. After transfection with a miR-146a-5p mimic, or si-TRAF6 or si-IRAK1, we observed that the mRNA and protein levels of NF-κB/p-NF-κB, NLRP3, Caspase-1, and pro-inflammatory cytokine in the HUVECs were all down-regulated, and the secretion of IL-6 from cells declined significantly. After transfection with a miR-146-5p mimic, the expression of TRAF6 and IRAK1 in HUVECs were both down-regulated. Dualluciferase reporter assays confirmed that miR-146-5p directly targets the 3'-untranslated region (3'-UTR) of TRAF6 and IRAK1 to regulate their expression.Conclusions: As a modulator of TRAF6 and IRAK1, miR-146a-5p negatively regulated LPS-induced NF-κB activation and the NLRP3 inflammasome signaling pathway in HUVECs. Thus, miRNA-146a-5p may serve as a potential therapeutic target for atherosclerosis.

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Section: Discussionmentioning

confidence: 52%

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Hou¹,

Deng²,

Deng

et al. 2021

Ann Transl Med

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“…These observations indicate that this miRNA is gaining novel targets and losing existing targets relatively rapidly, with neutral or potentially faster than neutral rates. Notably, miR-146 contributes to diverse immune system functions, including fever response, tumor suppression, T-cell homeostasis, and cytokine production in multiple immune cell lineages [71][72][73][74][75]. It is conceivable that miR-146 targets may be rapidly co-evolving with pathogens as part of an 'arms race' scenario that has frequently been seen in host-pathogen interactions [76].…”

Section: Patterns Of Target Site Loss and Gain For Individual Mirnasmentioning

confidence: 99%

Evolutionary dynamics of microRNA target sites across vertebrate evolution

et al. 2020

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MicroRNAs (miRNAs) control the abundance of the majority of the vertebrate transcriptome. The recognition sequences, or target sites, for bilaterian miRNAs are found predominantly in the 3 0 untranslated regions (3 0 UTRs) of mRNAs, and are amongst the most highly conserved motifs within 3 0 UTRs. However, little is known regarding the evolutionary pressures that lead to loss and gain of such target sites. Here, we quantify the selective pressures that act upon miRNA target sites. Notably, selective pressure extends beyond deeply conserved binding sites to those that have undergone recent substitutions. Our approach reveals that even amongst ancient animal miRNAs, which exert the strongest selective pressures on 3 0 UTR sequences, there are striking differences in patterns of target site evolution between miRNAs. Considering only ancient animal miRNAs, we find three distinct miRNA groups, each exhibiting characteristic rates of target site gain and loss during mammalian evolution. The first group both loses and gains sites rarely. The second group shows selection only against site loss, with site gains occurring at a neutral rate, whereas the third loses and gains sites at neutral or above expected rates. Furthermore, mutations that alter the strength of existing target sites are disfavored. Applying our approach to individual transcripts reveals variation in the distribution of selective pressure across the transcriptome and between miR-NAs, ranging from strong selection acting on a small subset of targets of some miRNAs, to weak selection on many targets for other miRNAs. miR-20 and miR-30, and many other miRNAs, exhibit broad, deeply conserved targeting, while several other comparably ancient miRNAs show a lack of selective constraint, and a small number, including mir-146, exhibit evidence of rapidly evolving target sites. Our approach adds valuable perspective on the evolution of miRNAs and their targets, and can also be applied to characterize other 3 0 UTR regulatory motifs.

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“…Since the mitochondrial alterations observed in the senescent cells represent etiopathogenetic factors in age-associated diseases, the deepening of the communication routes between nucleus (Buscaglia and Li, 2011;Ma et al, 2013) -PDCD4 (Matsuhashi et al, 2019) -Cell proliferation arrest-Proinflammatory cytokine production-Activation of NF-κB pathway and NLRP3 inflammasome -mt-Cyb (Li et al, 2016) -enhanced mitochondrial translation miR-146a-5p -TLR4 (Xiao et al, 2019) -TRAF6 (Taganov et al, 2006) -IRAK1 (Taganov et al, 2006) -BCL2 (Giuliani et al, 2018) - and mitochondria may lead to devise new preventive and therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence

et al. 2021

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Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential “messengers” of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.

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LPS induces CXCL16 expression in HUVECs through the miR-146a-mediated TLR4 pathway

Cited by 31 publications

References 25 publications

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs)

Evolutionary dynamics of microRNA target sites across vertebrate evolution

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence

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