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Inflammation pulmonaire et rôle des microARN dans la mucoviscidose

Abstract : In patients with cystic fibrosis (CF), at the pulmonary level, the ionic imbalance caused by CFTR chloride channel dysfunction promoting hyper-inflammation, whose regulatory mechanisms are altered. In this context, the NF-κB pathway is hyper-activated, but the origin of its deregulation remains uncertain. The aim of this work was to study the role of miRNA in pulmonary pathophysiology in CF patients. A small RNAseq analyse on bronchial epithelial cells cultured in air-liquid interface from CF patients and non-CF healthy subjects, allowed to identify miR-199a-3p, which is underexpressed in CF cells and regulates IKKβ directly and consequently the NF κB pathway activation and IL-8 secretion. In CF cells, miR-199a-3p origin is not due to pro-inflammatory context, nor CFTR intrinsic dysfunction but due to intracellular calcium concentration variation whose modulate the miR-199a-3p expression through one of the genes that synthesize it. Moreover, miR-199a-3p expression could be decreased following an infection by Pseudomonas aeruginosa, the most frequently found pathogen in CF airways. MiR-199a-3p can interact with others dysregulated miRNA in CF, the miR-636 and miR-9. MiR-636, an another miR identified by the small RNAseq, is overexpressed in CF cells and regulates negatively IL1R1 and IKKβ and positively RANK. Overexpression of miR-636 allows decreasing NF-κB pathway activation and IL-8, IL-6 secretions. MiR-199a-3p was a potential biomarker of plasma and miR-636 and miR-9 potential neutrophil biomarkers in CF patients vs non-CF. All these results illustrate the pivotal role of miRNA in lung inflammation in cystic fibrosis patients.
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Submitted on : Thursday, September 10, 2020 - 5:10:08 PM
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Pauline Bardin. Inflammation pulmonaire et rôle des microARN dans la mucoviscidose. Médecine humaine et pathologie. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS046⟩. ⟨tel-02935859⟩

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