Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma

Xu, Zhongli; Forno, Erick; Acosta‐Pérez, Edna; Han, Yueh‐Ying; Rosser, Franziska; Manni, Michelle L.; Canino, Glorisa; Chen, Wei; Celedón, Juan C.

doi:10.1111/pai.13776

Cited by 10 publications

(5 citation statements)

References 78 publications

(99 reference statements)

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“…A previous study in A549 cells investigated the overexpression of the Toll-like receptor (TLR), that has an important role in the innate immune system, and observed a decreased expression of among others CXCL10 and CCL20 in the cell supernatant due to the overexpression of TLR10, 88 similar to our findings in cell lysate. Furthermore, a meta-analysis of nasal epithelium from children between 6 and 16 years of age, demonstrated decreased expression of CXCL11 and CXCL10 in patients with obesity-related asthma 89 and is also in line with our hypothesis that the overexpression of CCL26 causes a more severe asthma phenotype, based on previous findings in nasal epithelium. 10 In a study of A549 cells infected with respiratory syncytial virus (RSV), higher concentrations of CXCL10 and CCL3 were identified in the cell supernatant 24 h after RSV infection.…”

Section: Discussionsupporting

confidence: 91%

The functional role of CST1 and CCL26 in asthma development

Hoyer,

Chakraborty,

Lilienthal

et al. 2024

Immunity Inflam & Disease

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BackgroundAsthma is the most common chronic disease in children with an increasing prevalence. Its development is caused by genetic and environmental factors and allergic sensitization is a known trigger. Dog allergens affect up to 30% of all children and dog dander‐sensitized children show increased expression of cystatin‐1 (CST1) and eotaxin‐3 (CCL26) in nasal epithelium. The aim of our study was to investigate the functional mechanism of CST1 and CCL26 in the alveolar basal epithelial cell line A549.MethodsA549 cells were transfected with individual overexpression vectors for CST1 and CCL26 and RNA sequencing was performed to examine the transcriptomics. edgeR was used to identify differentially expressed genes (= DEG, |log2FC | ≥ 2, FDR < 0.01). The protein expression levels of A549 cells overexpressing CST1 and CCL26 were analyzed using the Target 96 inflammation panel from OLINK (antibody‐mediated proximity extension–based assay; OLINK Proteomics). Differentially expressed proteins were considered with a |log2FC| ≥ 1, p < .05.ResultsThe overexpression of CST1 resulted in a total of 27 DEG (1 upregulated and 26 downregulated) and the overexpression of CCL26 in a total of 137 DEG (0 upregulated and 137 downregulated). The gene ontology enrichment analysis showed a significant downregulation of type I and III interferon signaling pathway genes as well as interferon‐stimulated genes. At the protein level, overexpression of CST1 induced a significantly increased expression of CCL3, whereas CCL26 overexpression led to increased expression of HGF, and a decrease of CXCL11, CCL20, CCL3 and CXCL10.ConclusionOur results indicate that an overexpression of CST1 and CCL26 cause a downregulation of interferon related genes and inflammatory proteins. It might cause a higher disease susceptibility, mainly for allergic asthma, as CCL26 is an agonist for CCR‐3‐carrying cells, such as eosinophils and Th2 lymphocytes, mostly active in allergic asthma.

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Section: Discussionsupporting

confidence: 91%

The functional role of CST1 and CCL26 in asthma development

Hoyer,

Chakraborty,

Lilienthal

et al. 2024

Immunity Inflam & Disease

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“…IL-15 has also been shown to promote Th2 differentiation and allergic sensitization in a mouse model of asthma 36 . Finally, induction of SOCS1 by PGAP3 may also be important to asthma as RNA-sequencing analysis of human nasal epithelial cells from children with asthma found significant expression of SOCS1 37 that is known to regulate cytokine signaling in both human bronchial epithelial cells from patients with asthma 38 and in the lungs of a mouse model of asthma 39 .…”

Section: Discussionmentioning

confidence: 99%

PGAP3 regulates human bronchial epithelial cell mRNAs present in asthma and respiratory virus reference data sets

Leslie,

Miller,

Lafuze

et al. 2024

Preprint

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PGAP3 is a glycosylphosphatidylinositol (GPI) phospholipase gene localized within chromosome 17q12-21, a region highly linked to asthma. Although much is known about the function of other chromosome 17q12-21 genes expressed at increased levels in bronchial epithelium such as ORMDL3 and GSDMB, little is known about the function of increased PGAP3 expression in bronchial epithelium in the context of asthma. The aim of this study was therefore to determine whether increased PGAP3 expression in human bronchial epithelial cells regulated expression of mRNA pathways important to the pathogenesis of asthma by utilizing RNA-sequencing and bioinformatic analysis. We performed RNA-sequencing on normal human bronchial epithelial cells transfected with PGAP3 for 24 and 48 hours. PGAP3 regulated genes were compared to asthma and respiratory virus (influenza A, rhinovirus, respiratory syncytial virus) reference data sets to identify PGAP3 target genes and pathways. Approximately 9% of the upregulated PGAP3-induced genes were found in an asthma reference data set, 41% in a rhinovirus reference data set, 33% in an influenza A reference data set, and 3% in a respiratory syncytial virus reference data set. PGAP3 significantly upregulated the expression of several genes associated with the innate immune response and viral signatures of respiratory viruses associated with asthma exacerbations. Two of the highest expressed genes induced by PGAP3 are RSAD2, OASL, and IFN-λ, which are anti-viral genes associated with asthma. PGAP3 also upregulated the antiviral gene BST2, which like PGAP3 is a GPI-anchored protein. We conclude that PGAP3 expression in human bronchial epithelial cells regulates expression of genes known to be linked to asthma, and also regulates the bronchial epithelial expression of genes pertinent to the pathogenesis of respiratory viral triggered asthma exacerbations.

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“…Different studies of peripheral blood white blood cells (WBCs) have identified epigenetic and transcriptomic changes in pathways related to immune signaling associated with obesity and asthma, lung function, and other related phenotypes (56,57). More recently, we reported a transcriptome-wide association study (TWAS) in nasal epithelium that found pronounced differences between obese children with asthma and their peers of healthy weight, with most genes related to interferon and non-T2 signaling pathways (58).…”

Section: F O R P U B L I C a T I O Nmentioning

confidence: 99%

Pediatric obesity-related asthma

Forno¹

2023

Pediatr Respir J

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There is significant epidemiological and experimental evidence of an association between obesity and asthma, both in children and adults. Children with obesity and asthma suffer from greater severity, worse symptom control, and overall lower quality of life. In this review, we examine some of the evidence relevant to pediatric "obese asthma" some of the underlying mechanisms, including the impact of obesity on lung function, systemic and airway inflammation, insulin resistance and the metabolic syndrome, and the role of genetic predisposition and genomic regulation. We then briefly review current recommendations for the management of these children, including in the management of their asthma and evidence for weight loss interventions. Finally, we highlight gaps and

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Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma

Cited by 10 publications

References 78 publications

The functional role of CST1 and CCL26 in asthma development

The functional role of CST1 and CCL26 in asthma development

PGAP3 regulates human bronchial epithelial cell mRNAs present in asthma and respiratory virus reference data sets

Pediatric obesity-related asthma

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