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ORMDL3-mediated bronchial epithelial pyroptosis leads to lung inflammatory in obese asthmatic mice

ABSTRACT: Obese asthma is a chronic disease that poses a serious threat to children's health, resulting in more severe wheezing, earlier airway remodelling, and insensitivity to hormone therapy. Despite its clinical importance, knowledge on the underlying mechanisms of this disease remains limited. This study aimed to elucidate the pathogenesis of obese asthmatic utilizing a murine model. The present study randomly divided thirty female BALB/c mice into three groups: normal mice, asthmatic mice, and obese asthmatic mice. The mice were fed a with high-fat diet (HFD) to induce obesity. Asthmatic mice were subjected to ovalbumin (OVA) sensitization and challenge. Mice with obesity were then subjected to OVA sensitization and challenge to develop obese asthmatic. Airway remodelling was observed in obese asthmatic mice. Proteomic and bioinformatics analyses were conducted on lung tissues from obese asthmatic and normal mice. A total of 200 proteins were differentially expressed in obese asthmatic compared to normal mice; of these, 53% were upregulated and 47% were downregulated. Pathway analysis revealed that obese asthmatic primarily affected the lysosome, phagosome, and sphingolipid metabolism pathways. In addition, pyroptosis was observed in obese asthmatic, along with significant increases in pyroptosis-related factors. Orosomucoid like 3 (ORMDL3), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin-D (GSDMD) expression was examined, with particularly high expression levels observed in obese asthmatic mice. In vitro experiments demonstrated that overexpression of ORMDL3 in human bronchial epithelial (HBE) cells led to increased expression of NLRP3, GSDMD, and cathepsin D (CTSD). These findings suggest that ORMDL3 may regulate pyroptosis and subsequent airway remodelling in obese asthmatic, possibly via CTSD/NLRP3/GSDMD pathway.

ORGANISM(S): Mus Musculus

SUBMITTER: Yan Sun

PROVIDER: PXD043630 | iProX | Fri Jul 07 00:00:00 BST 2023

REPOSITORIES: iProX

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ORMDL3‑mediated bronchial epithelial pyroptosis leads to lung inflammation in obese mice with asthma.

Liu Fan F Sun Yan Y Zhou Yun Y Gao Yuye Y Song Qijun Q Yang Jianmei J Xu Chao C Li Guimei G

Molecular medicine reports 20230818 4

Asthma associated with obesity is a chronic disease that poses a threat to health in children and results in severe wheezing, earlier airway remodeling and increased insensitivity to hormone therapy compared with those who only have asthma. Despite its clinical importance, knowledge on the underlying mechanisms of this disease is limited. The present study aimed to elucidate the pathogenesis of asthma associated with obesity using a murine model. A total of 30 female BALB/c mice were divided int ...[more]

PMID: 37594074

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Project description:Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness; Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 Âµm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) âinduced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naÃ¯ve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Experiment Overall Design: animals were treated by PBS, Oval albumin, PM, or both OVA/PM

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ORMDL3-mediated bronchial epithelial pyroptosis leads to lung inflammatory in obese asthmatic mice

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ORMDL3‑mediated bronchial epithelial pyroptosis leads to lung inflammation in obese mice with asthma.

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