Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [B]

ABSTRACT: T helper type 2 (Th2) responses are crucial for defense against infections by helminths and are responsible for the development of allergic reactions that can lead to severe clinical disorders, such as asthma or anaphylaxis, and ultimately to death. The induction of Th2 responses requires a specific activation process, triggered by specialized dendritic cells (DCs), by which naive CD4+ Th0 cells acquire the capacity to produce Th2 cytokines. However, the mechanistic basis of the functional specialization enabling DCs for the initiation of Th2 responses has remained elusive. Here we show that interleukin-4 (IL-4), a cytokine produced by basophils, mast cells and Th2-polarized CD4+ T helper cells, exerting a crucial function during anti-helminths and allergic Th2 responses, has a key role in the licensing/conditioning of DCs for the induction of Th2 responses, by bloking their potential to produce Th1-driving cytokines, such as IL-12, IL-18 and IL-23. Microarray analyses (duplicates) were used to compared the transcriptional profile of monocyte-derived dendritic cells (moDCs) cultured with GM-CSF in the absence or presence of interleukin-4: IL4-moDCs versus C-moDCs.

ORGANISM(S): Mus musculus

SUBMITTER: Juan Oliveros

PROVIDER: E-GEOD-39858 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation.

López-Bravo María M Minguito de la Escalera María M Domínguez Pilar M PM González-Cintado Leticia L del Fresno Carlos C Martín Pilar P Martínez del Hoyo Gloria G Ardavín Carlos C

The Journal of allergy and clinical immunology 20131017 6

<h4>Background</h4>Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in th ...[more]

PMID: 24139608

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Project description:Background: Allergic asthma is one of the chronic inflammatory diseases and is generally induced by CD4+ T helper 2 cells (Th2) in the context of persistent inhaled stimuli. Dendritic cells (DCs) are essential to mounting the Th2-mediated airway inflammation by presenting inhaled antigens to prime CD4+ T cells. Small extracellular vesicles (sEV) derived from mesenchymal stem cells (MSCs) exhibited great interest in intractable diseases. However, whether MSC-sEV play a role on DCs in airway inflammation is still unclear. Methods: We isolate MSC-sEV using anion-exchange chromatography. Mouse bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs) were used to study the effects of MSC-sEV on dendritic cell surface molecules and their cytokine release. Mice were sensitized with house dust mites (HDM) to induce airway inflammation, and treated with MSC-sEV, The effects of sEV on murine DCs were identified. Extracellular flux analysis techniques were used to study the effects of MSC-sEV on the metabolic state of dendritic cells. RNA sequencing to study altered gene expression in BMDCs after MSC-sEV treatment. Results: MSC-sEV mitigated the accumulation of Th2-associated moDCs in mouse lung in response to HDM. MSC-sEV also decreased the activation of moDCs induced in vitro including the expression of co-stimulatory molecules and cytokines secretion. Furthermore, we identified that DCs were able to take MSC-sEV in vitro and in vivo. Mechanistically, using bulk RNA-sequencing, we found that MSC-sEV played roles in the metabolic pathway of murine DCs. Using extracellular flux analysis, we found that MSC-sEV increased the requirement of oxidative phosphorylation on moDCs. Importantly, MSC-sEV displayed similar effects on human moDCs including decreased co-stimulatory molecular and cytokine production. Conclusions: MSC-sEV are able to alter the metabolic state of DCs, favoring DCs to maintain OXPHOS (oxidative phosphorylation) rather than glycolysis, thereby reducing DCs-initiated inflammatory responses and attenuating Th2 lung inflammation, suggesting MSC-sEV can be a potential clinical therapy for airway inflammation.

Project description:Human monocyte-derived dendritic cells (moDCs) have been used as an in vitro model for studying tolerance and immunity. However, the underlying metabolic states of tolerogenic (dexamethasone and vitamin D3-treated), immature and immunogenic (mature, LPS-treated) moDCs have not been completely characterized. Through transcriptomic analyses, we determined that tolerogenic moDCs exhibit augmented catabolic pathways with respect to oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis. Functionally, tolerogenic moDCs showed the highest mitochondrial membrane potential, production of reactive oxygen species and superoxide, and increased mitochondrial spare respiratory capacity. Tolerogenic and mature moDCs manifested differential FAO gene expression with FAO activity being significantly higher in tolerogenic and immature moDCs than in mature. In addition, tolerogenic and mature moDCs demonstrated similar levels of glycolytic rate, but not glycolytic capacity and reserve, which were more pronounced in tolerogenic and immature moDCs. Finally, tolerogenic and immature moDCs, but not mature moDCs, showed high plasticity to compensate the intracellular ATP content after inhibition of different energetic metabolic pathways. Overall, tolerogenic moDCs exhibit a metabolic signature of increased, stable OXPHOS programing and high plasticity for metabolic adaptation. These findings provide a framework for future research of metabolic properties of human DCs. Total RNA of sixteen samples from four moDC types (tolerogenic, LPS-tolerogenic, immature and mature) were extracted by Trizol (Invitrogen) followed by a clean-up procedure using RNeasy Micro Kit (Qiagen). All RNA samples had an integrity number ≥9.6 assessed by Agilent Bioanalyzer. Total RNA samples were amplified using TargetAmp™ and the biotinilated cRNA was prepared by Nano-g™ Biotin-aRNA Labeling Kit for the Illumina® System (Epicentre). After the hybridization to the Illumina Human HT-12 v4 Beadchips for 17 h at 58°C, the arrays were washed, stained (Illumina Wash Protocol) and then scanned using BeadArray Scanner 500GX. Array data were extracted at the probe level without background correction using Illumina GenomeStudio software. These raw data were quantile normalized and log2 transformed. Technical replicates were obtained from the hybridization in duplicate of three samples. Pearson correlation analysis showed high correlation between the technical replicates (r>0.99). Differentially expressed genes (DEGs) were identified using Limma16 with Benjamini-Hochberg multiple testing correction (p<0.05). DEGs were further clustered into different groups according to the patterns of expression change among the different moDC types using STEM software17. The analysis was performed in R v.2.12.2 (http://www.R-project.org) with Bioconductor 2.12 (http://www.bioconductor.org) and enabled by Pipeline Pilot (www.accelrys.com).

Dataset Information

Role of interleukin-4 in the licensing of dendritic cells for the induction of Th2 responses [B]

Publications

IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation.

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