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CDC42-related genes are upregulated in helper T cells from obese asthmatic children.

ABSTRACT: BACKGROUND:Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic TH1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying TH1-polarized inflammation are not well understood. OBJECTIVE:We compared the CD4+ T-cell transcriptome in obese children with asthma with that in normal-weight children with asthma to identify key differentially expressed genes associated with TH1-polarized inflammation. METHODS:CD4+ T-cell transcriptome-wide differential gene expression was compared between 21 obese and 21 normal-weight children by using directional RNA sequencing. High-confidence differentially expressed genes were verified in the first cohort and validated in a second cohort of 20 children (10 obese and 10 normal-weight children) by using quantitative RT-PCR. RESULTS:Transcriptome-wide differential gene expression among obese asthmatic children was enriched for genes, including VAV2, DOCK5, PAK3, PLD1, CDC42EP4, and CDC42PBB, which are associated with CDC42, a small guanosine triphosphate protein linked to T-cell activation. Upregulation of MLK3 and PLD1, genes downstream of CDC42 in the mitogen-activated protein kinase and mammalian target of rapamycin pathways and the inverse correlation of CDC42EP4 and DOCK5 transcript counts with FEV1/FVC ratio together support a role of CDC42 in the TH1 polarization and pulmonary function deficits found in patients with obesity-related asthma. CONCLUSIONS:Our study identifies the CDC42 pathway as a novel target that is upregulated in TH cells of obese asthmatic children, suggesting its role in nonatopic TH1-polarized systemic inflammation and pulmonary function deficits found in patients with pediatric obesity-related asthma.

SUBMITTER: Rastogi D

PROVIDER: S-EPMC5671374 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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CDC42-related genes are upregulated in helper T cells from obese asthmatic children.

Rastogi Deepa D Nico John J Johnston Andrew D AD Tobias Toni Adrianne M TAM Jorge Yurydia Y Macian Fernando F Greally John M JM

The Journal of allergy and clinical immunology 20170504 2

<h4>Background</h4>Pediatric obesity-related asthma is more severe and less responsive to medications than asthma in normal-weight children. Obese asthmatic children have nonatopic T<sub>H</sub>1-polarized systemic inflammation that correlates with pulmonary function deficits, but the pathways underlying T<sub>H</sub>1-polarized inflammation are not well understood.<h4>Objective</h4>We compared the CD4<sup>+</sup> T-cell transcriptome in obese children with asthma with that in normal-weight chil ...[more]

PMID: 28479334

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Project description:It has been reported that airway epithelial cells and ferroptosis have certain effect on asthma. However, the action mechanism of ferroptosis-related genes in airway epithelial cells of asthmatic patients is still unclear. Firstly, the study downloaded the GSE43696 training set, GSE63142 validation set and GSE164119 (miRNA) dataset from the gene expression omnibus database. 342 ferroptosis-related genes were downloaded from the ferroptosis database. Moreover, differentially expressed genes (DEGs) between asthma and control samples in the GSE43696 dataset were screened by differential analysis. Consensus clustering analysis was performed on asthma patients to classify clusters, and differential analysis was performed on clusters to obtain inter-cluster DEGs. Asthma-related module was screened by weighted gene co-expression network analysis. Then, DEGs between asthma and control samples, inter-cluster DEGs and asthma-related module were subjected to venn analysis for obtaining candidate genes. The last absolute shrinkage and selection operator and support vector machines were respectively applied to the candidate genes to screen for feature genes, and functional enrichment analysis was performed. Finally, a competition endogenetic RNA network was constructed and drug sensitivity analysis was conducted. There were 438 DEGs (183 up-regulated and 255 down-regulated) between asthma and control samples. 359 inter-cluster DEGs (158 up-regulated and 201 down-regulated) were obtained by screening. Then, the black module was significantly and strongly correlated with asthma. The venn analysis yielded 88 candidate genes. 9 feature genes (NAV3, ITGA10, SYT4, NOX1, SNTG2, RNF182, UPK1B, POSTN, SHISA2) were screened and they were involved in proteasome, dopaminergic synapse etc. Besides, 4 mRNAs, 5 miRNAs, and 2 lncRNAs collectively formed competition endogenetic RNA regulatory network, which included RNF182-hsa-miR-455-3p-LINC00319 and so on. The predicted therapeutic drug network map contained NAV3-bisphenol A and other relationship pairs. The study investigated the potential molecular mechanisms of NAV3, ITGA10, SYT4, NOX1, SNTG2, RNF182, UPK1B, POSTN, SHISA2 in airway epithelial cells of asthmatic patients through bioinformatics analysis, providing a reference for the research of asthma and ferroptosis.

Project description:BackgroundThe airway epithelium can express factors that drive subepithelial airway remodeling. TGF-?2, vascular epithelial growth factor (VEGF), a disintegrin and metalloprotease 33 (ADAM33), and periostin are hypothesized to be involved in subepithelial remodeling and are overexpressed in adult asthmatic airways. Epidemiologic data suggest that lung function deficits in asthmatic patients are acquired in childhood.ObjectivesWe sought to determine whether airway epithelial cells (AECs) from asthmatic children differentially express TGF-?2, VEGF, ADAM33, or periostin compared with cells from atopic nonasthmatic and healthy children intrinsically or in response to IL-4/IL-13 stimulation.MethodsBronchial and nasal epithelial cells were obtained from brushings from well-characterized asthmatic (n = 16), atopic nonasthmatic (n = 9), and healthy (n = 15) children after achievement of anesthesia for elective procedures. After differentiation at an air-liquid interface (ALI) for 3 weeks, conditioned media were sampled and RNA was extracted from unstimulated and IL-4/IL-13-stimulated cultures. TGF-?2 and VEGF levels were measured with ELISA. ADAM33 and periostin expression was assessed by using real-time PCR.ResultsTGF-?2 and VEGF production was significantly greater in bronchial and nasal ALI cultures from asthmatic children than in cultures from atopic nonasthmatic and healthy children. TGF-?2 levels increased significantly in asthmatic cultures after IL-4/IL-13 stimulation. Within-subject correlation between nasal and bronchial ALI production of TGF-?2 (r = 0.64, P = .001) and VEGF (r = 0.73, P < .001) was good. Periostin expression was 3.7-fold higher in bronchial cells (P < .001) and 3.9-fold higher in nasal cells (P < .004) from asthmatic children than in cells from atopic nonasthmatic or healthy children. ADAM33 was not differentially expressed by AECs from asthmatic patients compared with that from cells from atopic nonasthmatic or healthy children.ConclusionAECs from asthmatic children differentially express TGF-?2, VEGF, and periostin compared with cells from atopic nonasthmatic and healthy children. Nasal epithelial cells might be a suitable surrogate for bronchial cells that could facilitate investigation of the airway epithelium in future longitudinal pediatric studies.

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CDC42-related genes are upregulated in helper T cells from obese asthmatic children.

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CDC42-related genes are upregulated in helper T cells from obese asthmatic children.

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