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Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus.

ABSTRACT: MicroRNAs are important posttranscriptional regulators of gene expression, which have been shown to fine-tune innate immune responses downstream of pattern recognition receptor (PRR) signaling. This study identifies miR-650 as a novel PRR-responsive microRNA that is downregulated upon stimulation of primary human monocyte-derived dendritic cells (MDDCs) with a variety of different microbe-associated molecular patterns. A comprehensive target search combining in silico analysis, transcriptional profiling, and reporter assays reveals that miR-650 regulates several well-known interferon-stimulated genes, including IFIT2 and MXA. In particular, downregulation of miR-650 in influenza A infected MDDCs enhances the expression of MxA and may therefore contribute to the establishment of an antiviral state. Together these findings reveal a novel link between miR-650 and the innate immune response in human MDDCs.

SUBMITTER: Pichulik T

PROVIDER: S-EPMC4738369 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus.

Pichulik Tica T Khatamzas Elham E Liu Xiao X Brain Oliver O Delmiro Garcia Magno M Leslie Alasdair A Danis Benedicte B Mayer Alice A Baban Dilair D Ragoussis Jiannis J Weber Alexander N R AN Simmons Alison A

European journal of immunology 20151030 1

MicroRNAs are important posttranscriptional regulators of gene expression, which have been shown to fine-tune innate immune responses downstream of pattern recognition receptor (PRR) signaling. This study identifies miR-650 as a novel PRR-responsive microRNA that is downregulated upon stimulation of primary human monocyte-derived dendritic cells (MDDCs) with a variety of different microbe-associated molecular patterns. A comprehensive target search combining in silico analysis, transcriptional p ...[more]

PMID: 26460926

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Project description:BackgroundMicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in diverse biological processes via regulation of gene expression including in skeletal muscles. In the current study, miRNA expression profile was investigated in longissimus muscle biopsies of malignant hyperthermia syndrome-negative Duroc and Pietrain pigs with distinct muscle metabolic properties in order to explore the regulatory role of miRNAs related to mitochondrial respiratory activity and metabolic enzyme activity in skeletal muscle.ResultsA comparative analysis of the miRNA expression profile between Duroc and Pietrain pigs was performed, followed by integration with mRNA profiles based on their pairwise correlation and computational target prediction. The identified target genes were enriched in protein ubiquitination pathway, stem cell pluripotency and geranylgeranyl diphosphate biosynthesis, as well as skeletal and muscular system development. Next, we analyzed the correlation between individual miRNAs and phenotypical traits including muscle fiber type, mitochondrial respiratory activity, metabolic enzyme activity and adenosine phosphate concentrations, and constructed the regulatory miRNA-mRNA networks associated with energy metabolism. It is noteworthy that miR-25 targeting BMPR2 and IRS1, miR-363 targeting USP24, miR-28 targeting HECW2 and miR-210 targeting ATP5I, ME3, MTCH1 and CPT2 were highly associated with slow-twitch oxidative fibers, fast-twitch oxidative fibers, ADP and ATP concentration suggesting an essential role of the miRNA-mRNA regulatory networking in modulating the mitochondrial energy expenditure in the porcine muscle. In the identified miRNA-mRNA network, a tight relationship between mitochondrial and ubiquitin proteasome system at the level of gene expression was observed. It revealed a link between these two systems contributing to energy metabolism of skeletal muscle under physiological conditions.ConclusionsWe assembled miRNA-mRNA regulatory networks based on divergent muscle properties between different pig breeds and further with the correlation analysis of expressed genes and phenotypic measurements. These complex networks relate to muscle fiber type, metabolic enzyme activity and ATP production and may contribute to divergent muscle phenotypes by fine-tuning the expression of genes. Altogether, the results provide an insight into a regulatory role of miRNAs in muscular energy metabolisms and may have an implication on meat quality and production.

Project description:BackgroundInflammatory response after myocardial infarction (MI) is essential for cardiac healing, whereas excessive and prolonged inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanistic insight of these tightly controlled inflammatory processes has a significant impact on post-MI recovery and therapy. Here, we uncover the critical role of small GTPase RhoE in post-MI recovery and its clinical implication.MethodsThree genetic mouse lines are used: global RhoE knockout, cardiomyocyte-specific RhoE heterozygous, and cardiomyocyte-specific RhoE overexpression mice. A set of molecular signaling experiments, including bimolecular fluorescence complementation, immunoprecipitation, electrophoretic mobility shift assay, and mRNA microarray analysis, were conducted. Permanent ligation of the left anterior descending artery was performed, followed by the assessments of cardiac function, inflammation, and survival in the first week after MI. Finally, we examined the correlation of the expression levels of RhoE in MI patient heart and patient prognosis.ResultsRhoE deficiency turns on a group of proinflammatory gene expressions in mouse heart. Mice with cardiomyocyte-specific haploinsufficiency exhibit excessive inflammatory response with deleterious cardiac function after MI. A profound increase in nuclear factor-κB activity is detected in the mutant heart and the isolated cardiomyocytes. We further find that the expression of RhoE is upregulated in response to MI. Mechanistically, RhoE interacts with p65 and p50 individually in cytosol and blocks their nuclear translocation. RhoE also occupies the dimerization domain of p65 and subsequently disrupts the heterodimerization between p65 and p50. Cardiac RhoE overexpression inhibits nuclear factor-κB activity, restrains post-MI inflammation, and improves cardiac function and survival. Consistently, we find that the expression level of RhoE is elevated in the heart of patients with MI and that the patients with a higher expression level of RhoE exhibit a better prognosis in cardiac function recovery.ConclusionsThe study uncovers RhoE as a new fine-tuning factor modulating MI-induced inflammation and promoting injured heart recovery. RhoE may serve as a new potential biomarker for the assessment of MI patient prognosis. Manipulation of RhoE could be as a potential therapeutic approach for MI and other inflammatory diseases.

Dataset Information

Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus.

Publications

Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus.

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