PRMT1; C/EBPs; Airway wall remodelling; regulation of microRNA cluster 17-92; Mitochondria; Asthma
Sun Qingzhu, Fang Lei, Roth Michael, Tang Xuemei, Papakonstantinou Eleni, Zhai Weiqi, Louis Renaud, Heinen Vincent, Schleich Florence N., Lu Shemin, Savic Spasenjia, Tamm Michael, Stolz Daiana (2019), Bronchial thermoplasty decreases airway remodelling by blocking epithelium-derived heat shock protein-60 secretion and protein arginine methyltransferase-1 in fibroblasts, in European Respiratory Journal
, 54(6), 1900300-1900300.
Jin Ai, Bao Rujuan, Roth Michael, Liu Li, Yang Xudong, Tang Xuemei, Yang Xiaojun, Sun Qingzhu, Lu Shemin (2019), microRNA‐23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts, in Journal of Cellular Physiology
Fang Lei, Wang Xinggang, Sun Qingzhu, Papakonstantinou Eleni, S’ng Chongteck, Tamm Michael, Stolz Daiana, Roth Michael (2019), IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling, in International Journal of Molecular Sciences
, 20(4), 875-875.
Sun Qingzhu, Fang Lei, Tang Xuemei, Lu Shemin, Tamm Michael, Stolz Daiana, Roth Michael (2018), TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts, in The Journal of Immunology
, 202(1), 37-47.
The prevalence of asthma is continuously increasing worldwide as announced on the 6th March 2017 by the World Health Organization and in the State of Global Air 2017 Report (Health Effect Institute Boston, USA). The latter report points out that majority of people lives in polluted air which causes re-occurring episodes of lung inflammation and can lead to asthma. In 2016, The EU Symposium on the Awareness of Allergy declared that: “chronic airway diseases are a major and growing health problem in Europe”.Asthma is the most prevalent chronic airway disease affecting 8 % of the world’s population and the number of patient doubles every 10 years. Despite being a heterogeneous disease, the major pathologies are chronic airway inflammation and airway wall remodeling. In most patients inflammation can be well controlled by anti-inflammatory drugs, but airway wall thickening cannot be reduced by any available drug. Today, only bronchial thermoplasty in severe asthma showed lasting symptom relief after reducing airway wall thickness by destroying sub-epithelial mesenchymal cells. Therefore, leading experts in the field recently suggested that unless the mechanism driving airway wall remodeling is better understood, there will be no cure for asthma. Airway wall remodeling includes: (a) dysfunction of the bronchial epithelium, (b) hypertrophy / hyperplasia of sub-epithelial mesenchymal cells, (d) increased mitochondrial activity, and (d) increased deposition of sub-epithelial extracellular matrix. New clinical studies showed that sub-epithelial mesenchymal cells release pro-inflammatory cytokines that recruit immune cells into the airways. We and others demonstrated that remodeling of human asthmatic airway smooth muscle cells and fibroblasts is due to increased Erk1/2 MAP kinase activity, PRMT1 expression and mitochondrial mass, which are the consequence of reduced C/EBP-a expression and low levels of microRNA-19a.These studies were performed in cells isolated from more than 150 asthma patients which were collected at six hospitals from Switzerland (Basel), Italy (Naples), Belgium (Liege), Canada (Manitoba), and Australia (Sydney: Royal Prince Alfred Hospital, Royal North Shore Hospital).Referring to our earlier studies, we aim to prove that the expression of microRNA cluster 17-92 members is controlled by the ratio of C/EBP-a to C/EBP-ß. We hypothesize that the earlier reported low level of C/EBP-a in asthmatic smooth muscle cells increases the binding of C/EBP-ß to the microRNA cluster 17-92 promoter and leads to remodeling. This hypothesis will be tested in tissue sections and in isolated, diseased versus non-diseased human airway smooth muscle cells and fibroblasts. We will assess: 1) the functional link of the C/EBP-a to C/EBP-ß ratio on the expression of microRNA cluster 17-92 members. 2) the mechanism by which how C/EBP-a and -ß regulate the microRNA cluster 17-92 promoter activity by electrophoretic DNA mobility shift assay, DNA-protein precipitation assay, and luciferase reporter construct. 3) the consequence of C/EBP-a and/or C/EBP-ß knock-out in airway cells on microRNA cluster 17-92 control of Erk1/2 MAPK activity, STAT1 activity and PRMT1 expression; and 4) on mitochondria mass, mitochondrial activity, cell proliferation and extra cellular matrix deposition which all indicate remodeling. We are aware that other microRNAs had been linked to asthma, but most of those studies were focused on immune cell biology rather than on airway wall remodeling.We are confident that this study will provide new insight into the cause of airway wall remodeling in asthma and thus, provide the basis to develop new curative therapeutic strategies.