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LncRNA expression analysis in patients with eosinophilic and neutrophilic asthma

ABSTRACT: Long non-coding RNA (lncRNA) are known to be important in many diseases. There has been some reports that lncRNA take part in the pathogenesis of systemic inflammation of asthma. lncRNA regulates gene transcription, protein expression and epigenetic regulation. However, the lncRNAs associated with differently airway phenotype such as eosinophilic and neutrophilic asthma remains unknown. We aimed at identifying the differences in circulating lncRNA signature in Eos and Neu samples. lncRNA expression were studied between blood samples from Eos patients, Neu patients and healthy individuals (Control). Bioinformatic analysis was used to describe relevant biological pathways. Using quantitative real-time PCR, lncRNA expression was measured. Comparing with Control samples, Eos sample has 190 own lncRNA and Neu sample has 166 own lncRNA(difference ≥ 2-fold). KEGG pathway annotation data and GO terms revealed that several lncRNAs are possibly associated with respective phenotype. lncRNA was identifying to differ significantly between Eos and Neu samples by using qRT-PCR. The results show us that lncRNA may be involved in different phenotypes of asthma. Whether we can recognize different phenotypes of asthma through these lncRNA (as biomarkers) needs further study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117038 | GEO | 2019/04/09

REPOSITORIES: GEO

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Project description:Asthma is a complex, chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Distinct inflammatory phenotypes of eosinophilic, mixed, neutrophilic and paucigranulocytic asthma are identified in patients, but most in vivo mouse models, studying asthma mechanisms, mimic only eosinophilic phenotype in humans. The detailed unbiased in vivo studies on molecular responses among different kinds of inflammation in asthma models are lacking. Therefore, we developed mouse models representing three different inflammatory phenotypes of airway inflammation, namely eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitisation. We used microarrays to determine the global gene expression in the lungs of mice with eosinophilic, mixed and neutrophilic inflammatory phenotypes to uncover underlying differences in clinical presentation and to find novel molecular targets and pathways, which might reflect different molecular mechanisms of the disease. By whole genome transcriptome profiling, we found that airway tight junction (TJ) molecules, mucins and inflammasome-related genes are differentially expressed in distinct phenotypes of allergic airway inflammation. Next, detailed analysis of several molecules from these families by quantitative RT-PCR, western blot and confocal microscopy revealed that (i) Zo-1 and Cldn18 were downregulated in all phenotypes, while Cldn4 upregulation was characteristic for neutrophilic airway inflammation; (ii) mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic asthma, and (iii) upregulation of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1 and IL-1b was characteristic for neutrophilic asthma. Finally, we showed that inflammasome/Th-17/neutrophilic axis cytokines, namely IL-1b and IL-17 impaired epithelial barrier function and increased mucins expressions in primary human bronchial epithelial cells from normal and asthmatic donors. Our findings suggest that differential expression of TJs, mucins and inflammasome-related molecules in distinct asthma phenotypes could be mechanistically linked and might further reflect the differences observed in the clinic.

Project description:Background: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published. Methods: We conducted a genome-wide analysis of microRNA and messenger RNA (mRNA) in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis (WGCNA) was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes, and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway. Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for toll-like receptor (TLR) and Th17 signaling, and endoplasmic reticulum stress. Hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma. Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.

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LncRNA expression analysis in patients with eosinophilic and neutrophilic asthma

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