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MiRNA expression profiling of murine LPS-stimulated dendritic cells exposed to quercetin

ABSTRACT: Dendritic cells (DCs) are the most potent antigen-presenting cells that play an important role in the crosstalk between the innate and the adaptive immune response. We identified quercetin exposure as an effective strategy to suppress DCs inflammatory response induced by LPS. In this study, using NGS analysis, we examined the effect of quercetin on miRNAs expression in DCs. We defined a signature of 113 miRNAs differentially regulated in LPS-stimulated DCs after quercetin exposure. Among them, we observed an upregulation of miR-369-3p that potentially regulated C/EBP-beta. We functionally demonstrate that the loss of function of miR-369-3p in LPS-stimulated DCs during quercetin exposure led to an increase of C/EBP-beta and its downstream targets TNFα and IL6. Conversely, we showed that the ectopic induction of miR-369-3p even without quercetin suppresses the inflammatory response of LPS reducing C/EBP-beta, TNFα and IL6 production. In vivo, oral administration of quercetin induces miR-369-3p expression. These data demonstrate that a key mediator of immunosuppressive effect of quercetin is miR-369-3p. These findings could have potentially therapeutic implications since the induction of miR-369-3p expression may have anti-inflammatory effect.

ORGANISM(S): Mus musculus

PROVIDER: GSE112327 | GEO | 2019/12/31

REPOSITORIES: GEO

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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MiRNA expression profiling of murine LPS-stimulated dendritic cells exposed to quercetin

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