miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD

Osei, Emmanuel T.; Florez-Sampedro, Laura; Tasena, Hataitip; Faiz, Alen; Noordhoek, Jacobien A.; Timens, Wim; Postma, Dirkje S.; Hackett, Tillie L.; Heijink, Irene H.; Brandsma, Corry‐Anke

doi:10.1183/13993003.02538-2016

Cited by 52 publications

(54 citation statements)

References 34 publications

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“…This common G>C SNP in pre-miR-146a-5p has been associated with decreased expression of the mature miR-146a-5p [11]. Unexpectedly, in the present study, a lower miR-146a-5p expression was observed in fibroblasts from donors homozygous for the G allele of SNP rs2910164, which were all but one COPD patient [5]. A validation study in a large independent cohort will be needed to verify these results.…”

supporting

confidence: 50%

“…Importantly, this increase of miR-146a-5p was impaired in fibroblasts from patients with COPD, which releases the brake on the IL-1R/NF-κB pathway and is likely to contribute to the abnormal inflammation in COPD. Interestingly, treating fibroblasts with an miR-146a-5p mimic downregulated the expression of IRAK-1, resulting in a reduced release of IL-8 and confirming the anti-inflammatory role of miR-146a-5p [5]. It is worth noting that the inability of COPD fibroblasts to upregulate miR-146a-5p not only leads to an impaired negative feedback regulation of NF-κB signalling, but also results in a reduced mRNA degradation and thus prolonged half-life of cyclooxygenase (COX)-2, another target of miR-146a-5p [10].…”

mentioning

confidence: 68%

“…et al [5] demonstrated that epithelial-derived IL-1α induces miR-146a-5p expression in fibroblasts. Importantly, this increase of miR-146a-5p was impaired in fibroblasts from patients with COPD, which releases the brake on the IL-1R/NF-κB pathway and is likely to contribute to the abnormal inflammation in COPD.…”

mentioning

confidence: 99%

“…In an attempt to find the mechanism explaining the inability of COPD lung fibroblasts to upregulate miR-146a-5p, OSEI et al [5] assessed the presence of the single nucleotide polymorphism (SNP) rs2910164 in their primary lung fibroblasts. This common G>C SNP in pre-miR-146a-5p has been associated with decreased expression of the mature miR-146a-5p [11].…”

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confidence: 99%

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MicroRNAs as future therapeutic targets in COPD?

Bracke

Mestdagh

2017

Eur Respir J

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]. Chronic obstructive pulmonary disease (COPD) represents a major cause of chronic morbidity and mortality, affecting more than 200 million people worldwide and leading to approximately 3 million deaths each year. COPD is mainly caused by cigarette smoking and is characterised by a chronic inflammation leading to obstruction of the small airways and destruction of lung parenchyma (emphysema). Therapies that slow down the accelerated decline in lung function in patients with COPD are still lacking. Therefore, it is essential to unravel the mechanistic processes that underlie the inflammatory reaction and subsequent structural changes in COPD [1]. Aberrant cross-talk between epithelial and mesenchymal cells has been associated with inflammatory and remodelling processes in COPD. OSEI et al. [2] previously demonstrated that airway epithelial cells (AECs) from COPD patients release more interleukin (IL)-1α upon in vitro exposure to cigarette smoke extract. Moreover, using an elegant co-culture model, they demonstrated that this epithelial-derived IL-1α induced a pro-inflammatory lung fibroblast phenotype, releasing high amounts of the neutrophil attracting chemokine IL-8 [2]. Interestingly, we and others have reported increased levels of IL-1α in the lungs of patients with COPD and have shown in in vivo cigarette smoke models that neutrophilic inflammation is strongly dependent on IL-1α [3, 4]. In the current issue of the European Respiratory Journal, OSEI et al. [5] demonstrate that the dysfunctional cross-talk between AECs and fibroblasts in COPD is due to the impaired ability of COPD fibroblasts to upregulate microRNA-146a-5p. MicroRNAs (miRNAs) are endogenous, small noncoding RNAs with a regulatory function on gene expression. They bind in a sequence-specific manner to sites with imperfect complementarity in target messenger RNAs (mRNAs), leading to direct inhibition of protein translation or degradation of the transcript. In this way, miRNAs can interact with hundreds of genes simultaneously and regulate several developmental and physiological processes, including cellular proliferation, differentiation, apoptosis and innate and adaptive immune responses [6]. miR-146a-5p has frequently emerged as a regulator of inflammation [7]. Upon activation of several inflammatory pathways, such as Toll-like receptor (TLR) or IL-1R signalling, miR-146a-5p is induced in a nuclear factor (NF)-κB-dependent manner [8]. By targeting key molecules downstream of TLR and IL-1R pathways like tumour necrosis factor receptor-associated factor-6 and IL-1 receptor-associated kinase (IRAK)-1, it functions as a negative feedback regulator, limiting the intensity and duration of the inflammatory response [9]. In their co-cultures of airway epithelial cells and primary lung fibroblasts, OSEI

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supporting

confidence: 50%

mentioning

confidence: 68%

mentioning

confidence: 99%

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confidence: 99%

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MicroRNAs as future therapeutic targets in COPD?

Bracke

Mestdagh

2017

Eur Respir J

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“…Notably, miR-146a-5p was previously reported to be involved in airway inflammation associated with smoking and COPD [10] and to inhibit MUC5AC production in vitro [21]. We recently found miR-146a-5p to be higher expressed in non-COPD lung fibroblasts upon co-culture with bronchial epithelial cells, while there was significantly less increase in COPD fibroblasts, suggesting a role for miR-146a-5p in disturbed epithelial-fibroblast crosstalk in COPD [22]. Our present findings suggest that miR-146a-5p may also be involved in mucus hypersecretion via epithelial-fibroblast crosstalk; however, it is not yet clear via which target gene nor in which cell type it has its main effect on CMH.…”

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confidence: 85%

microRNA–mRNA regulatory networks underlying chronic mucus hypersecretion in COPD

et al. 2018

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Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. and were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of -related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including and , as potential key miRNA-mRNA networks regulating CMH in COPD.

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Long non‐coding RNA PVT1, a novel biomarker for chronic obstructive pulmonary disease progression surveillance and acute exacerbation prediction potentially through interaction with microRNA‐146a

Wang

Lyu

et al. 2020

Clinical Laboratory Analysis

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Objective This study aimed to investigate the abilities of long non‐coding RNA PVT1 (lnc‐PVT1) and microRNA‐146a (miR‐146a) in predicting chronic obstructive pulmonary disease (COPD) susceptibility and acute exacerbation risk, moreover, to explore the association of lnc‐PVT1 with disease severity, inflammation, and miR‐146a in patients with COPD. Methods A total of 80 acute exacerbation of COPD (AECOPD) patients, 80 stable COPD patients, and 80 healthy controls (HCs) were consecutively recruited. Peripheral blood samples of all participants were collected to isolate peripheral blood mononuclear cells (PBMCs), and serum: PBMCs were used to detect lnc‐PVT1 and miR‐146a by RT‐qPCR; serum was used to detect inflammatory cytokines by ELISA. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage of COPD was assessed. Results Lnc‐PVT1 expression was highest in AECOPD patients, followed by stable COPD patients and HCs. Receiver operating characteristic curves disclosed that lnc‐PVT1 distinguished AECOPD patients and stable COPD patients from HCs, also distinguished AECOPD patients from stable COPD patients. In AECOPD patients and stable COPD patients, lnc‐PVT1 expression positively correlated with GOLD stage and levels of TNF‐α, IL‐6, IL‐8, and IL‐17. Moreover, lnc‐PVT1 was negatively correlated with miR‐146a. For miR‐146a, its expression was lowest in AECOPD patients, followed by stable COPD patients and HCs, and it predicted reduced COPD susceptibility and decreased acute exacerbation risk; meanwhile, it negatively correlated with GOLD stage and inflammatory cytokine levels in AECOPD patients and stable COPD patients. Conclusion Lnc‐PVT1 assists the disease management and acute exacerbation risk monitoring of COPD via interaction with miR‐146a.

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miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD

Cited by 52 publications

References 34 publications

MicroRNAs as future therapeutic targets in COPD?

MicroRNAs as future therapeutic targets in COPD?

microRNA–mRNA regulatory networks underlying chronic mucus hypersecretion in COPD

Long non‐coding RNA PVT1, a novel biomarker for chronic obstructive pulmonary disease progression surveillance and acute exacerbation prediction potentially through interaction with microRNA‐146a

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