The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium

Schaefer, Niccolette; Li, Xingnan; Seibold, Max A.; Jarjour, Nizar N.; Denlinger, Loren C.; Castro, Mario; Coverstone, Andrea M.; Teague, W. Gerald; Boomer, Jonathan S.; Bleecker, Eugene R.; Meyers, Deborah A.; Moore, Wendy C.; Hawkins, Gregory A.; Fahy, John V.; Phillips, Brenda R.; Mauger, David T.; Dakhama, Azzeddine; Gellatly, Shaan L.; Pavelka, Nicole; Berman, Reena; Di, Y. Peter; Wenzel, Sally E.; Chu, Hong Wei

doi:10.1172/jci.insight.127237

Cited by 31 publications

(17 citation statements)

References 37 publications

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“…Bacterial permeability family member A1 (BPIFA1) is abundantly expressed in normal airway surface liquid and involved in the anti-inflammatory response. Thaikoottathil et al found that BPIFA1 inhibited airway eosinophilic inflammation by reducing eotaxin-2 production in alveolar macrophages (Thaikoottathil et al, 2012), which was consistent with Schaefer's research (Schaefer et al, 2019). γ-glutamyl-hydrolase (GGH) is a ubiquitously expressed enzyme that regulates cell proliferation, DNA synthesis, and repair.…”

Section: Discussionsupporting

confidence: 52%

A Potential circRNA-miRNA-mRNA Regulatory Network in Asthmatic Airway Epithelial Cells Identified by Integrated Analysis of Microarray Datasets

Chen

et al. 2021

Front. Mol. Biosci.

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Background: Asthma is one of the most prevalent chronic respiratory diseases worldwide. Bronchial epithelial cells play a critical role in the pathogenesis of asthma. Circular RNAs (circRNAs) act as microRNA (miRNA) sponges to regulate downstream gene expression. However, the role of epithelial circRNAs in asthma remains to be investigated. This study aims to explore the potential circRNA-miRNA-messenger RNA (mRNA) regulatory network in asthma by integrated analysis of publicly available microarray datasets.Methods: Five mRNA microarray datasets derived from bronchial brushing samples from asthma patients and control subjects were downloaded from the Gene Expression Omnibus (GEO) database. The robust rank aggregation (RRA) method was used to identify robust differentially expressed genes (DEGs) in bronchial epithelial cells between asthma patients and controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to annotate the functions of the DEGs. Protein-protein interaction (PPI) analysis was performed to identify hub genes. Three miRNA databases (Targetscan, miRDB, and miRWalk) were used to predict the miRNAs which potentially target the hub genes. A miRNA microarray dataset derived from bronchial brushings was used to validate the miRNA-mRNA relationships. Finally, a circRNA-miRNA-mRNA network was constructed via the ENCORI database.Results: A total of 127 robust DEGs in bronchial epithelial cells between steroid-naïve asthma patients (n = 272) and healthy controls (n = 165) were identified from five mRNA microarray datasets. Enrichment analyses showed that DEGs were mainly enriched in several biological processes related to asthma, including humoral immune response, salivary secretion, and IL-17 signaling pathway. Nineteen hub genes were identified and were used to construct a potential epithelial circRNA-miRNA-mRNA network. The top 10 competing endogenous RNAs were hsa_circ_0001585, hsa_circ_0078031, hsa_circ_0000552, hsa-miR-30a-3p, hsa-miR-30d-3p, KIT, CD69, ADRA2A, BPIFA1, and GGH.Conclusion: Our study reveals a potential role for epithelial circRNA-miRNA-mRNA network in the pathogenesis of asthma.

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Section: Discussionsupporting

confidence: 52%

A Potential circRNA-miRNA-mRNA Regulatory Network in Asthmatic Airway Epithelial Cells Identified by Integrated Analysis of Microarray Datasets

Chen

et al. 2021

Front. Mol. Biosci.

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“…There were 45 significantly enriched IPA pathways (Table S7), including 17 found in bulk cell analysis and 28 unique ones to AT2 cells (e.g., AhR Signaling/Xenobiotic Metabolism AHR Signaling Pathway). Several genes, Areg 40 and Bpifa1 41 , Hspa8 42 and Lgals3 43 (also DEGs in ciliated cells), have previously been linked to asthma.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation

Zhu¹,

Brown²,

Cai³

et al. 2021

Preprint

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Background: Tet1 protects against house dust mite (HDM)-induced lung inflammation in mice and alters the lung methylome and transcriptome. We explored the role of Tet1 in individual lung epithelial cell types in HDM-induced inflammation. Methods: A model of HDM-induced lung inflammation was established in Tet1 knockout and littermate wildtype mice. EpCAM+ lung epithelial cells were isolated. Libraries were generated using the 10X Chromium workflow and sequenced. ScRNA-seq analysis was performed using Cell Ranger, scAlign, and Seurat. Cell types were labeled using known markers. Enriched pathways were identified using Ingenuity Pathway Analysis. Transcription factor (TF) activity was analyzed by DoRothEA. Single-cell trajectory analysis was performed with Monocle to explore Alveolar type 2 (AT2) cell differentiation. Results: AT2 cells were the most abundant among the eight EpCAM+ lung epithelial cell types. HDM challenge increased the percentage of alveolar progenitor cells (AP), broncho alveolar stem cells (BAS), and goblet cells, and decreased the percentage of AT2 and ciliated cells. Bulk and cell-type-specific analysis identified genes subject to Tet1 regulation and linked to augmented lung inflammation, including alarms, detoxification enzymes and oxidative stress response genes, and gene in tissue repair. The transcriptomic regulation was accompanied by alterations in TF activities. Trajectory analysis supports that HDM may enhance the differentiation of AP and BAS cells into AT2 cells, independent of Tet1. Conclusions: Collectively, lung epithelial cells had common and unique transcriptomic signatures of allergic lung inflammation. Tet1 deletion altered transcriptomic networks in various lung epithelial cells, with an overall effect of promoting allergen-induced lung inflammation.

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“…Interestingly, nasal AECs isolated from subjects with asthma (Severe Asthma Research Program 3 cohort) carrying CC allele expressed less SPLUNC1, which negatively correlated with the severity of the disease (asthma endpoints such as FEV%, fractional exhaled nitric oxide, and serum IgE) as compared with CT and TT genotypes ( 73 ). Moreover, IL13-induced increased eotaxin-3 production in AECs by CC genotype is reversed by rSPLUNC1 treatment.…”

Section: Discussionmentioning

confidence: 99%

Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging

Jaiswal

Yadav

Makhija

et al. 2022

American Journal of Physiology-Lung Cellular and Molecular Phys

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Asthma and its heterogeneity changes with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adult asthmatics. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we employed a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adults (20-22 weeks) and aged (80-82 weeks) mice. Our result indicates an age-dependent increase in AHR, mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNAseq experiments of the aged lung revealed SPLUNC1 (Short Palate, Lung, and Nasal Epithelial Clone 1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.

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The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epithelium

Cited by 31 publications

References 37 publications

A Potential circRNA-miRNA-mRNA Regulatory Network in Asthmatic Airway Epithelial Cells Identified by Integrated Analysis of Microarray Datasets

A Potential circRNA-miRNA-mRNA Regulatory Network in Asthmatic Airway Epithelial Cells Identified by Integrated Analysis of Microarray Datasets

Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation

Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging

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