UPR modulation of host immunity by Pseudomonas aeruginosa in cystic fibrosis
| Autor: | Brahmchetna Bedi, Nicholas M. Maurice, C. Michael Hart, Arlene A. Stecenko, Joanna B. Goldberg, Kuo Chuan Lin, Ruxana T. Sadikot, Kaiser M. Bijli, Zhihong Yuan, Michael Koval |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
beta-Defensins Cystic Fibrosis Peroxisome proliferator-activated receptor Cystic fibrosis Article 03 medical and health sciences 0302 clinical medicine medicine Humans Pseudomonas Infections Protein kinase A chemistry.chemical_classification Innate immune system Pioglitazone biology Aryldialkylphosphatase Interleukin-8 Epithelial Cells General Medicine Endoplasmic Reticulum Stress medicine.disease Protein kinase R Immunity Innate Cystic fibrosis transmembrane conductance regulator Mitochondria PPAR gamma 030104 developmental biology chemistry A549 Cells 030220 oncology & carcinogenesis Host-Pathogen Interactions Pseudomonas aeruginosa Unfolded Protein Response biology.protein Unfolded protein response Cancer research Signal transduction Transcription Factor CHOP |
| Zdroj: | Clin Sci (Lond) |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Cystic fibrosis (CF) is a progressive multi organ autosomal recessive disease with devastating impact on the lungs caused by derangements of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Morbidity and mortality in CF are largely caused by lung complications due to the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. P. aeruginosa is a main respiratory pathogen in individuals with CF infecting most patients in later stages. Despite its recognized clinical impact, the molecular mechanisms that underlie P. aeruginosa pathogenesis and the host response to P. aeruginosa infection remain incompletely understood. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) an important modulator of inflammation and host defense, has shown to be reduced in CF airways. In this study we sought to investigate the upstream mechanisms repressing PPARγ expression and its impact on airway epithelial host defense. Endoplasmic Reticulum-stress (ER-stress) triggered unfolded protein response (UPR) activated by misfolded CFTR and P. aeruginosa infection contributed to attenuated expression of PPARγ. Specifically, the PERK signaling pathway lead to the enhanced expression of the CCAAT-enhancer-binding-protein homologous protein (CHOP). CHOP induction led to the repression of PPARγ expression. Mechanistically, we show that CHOP induction mediated PPARγ attenuation, impacted the innate immune function of normal, ΔF508 primary airway epithelial as well as bronchial epithelial cells by reducing expression of anti-microbial peptide (AMP) and paraoxanse-2 (PON-2), as well as enhancing IL-8 expression. Furthermore, mitochondrial reactive oxygen species production (mt-ROS) and ER stress positive feedforward loop also dysregulated mitochondrial bioenergetics. Additionally, our findings implicate that PPARγ agonist pioglitazone (PIO) has beneficial effect on the host at the multicellular level ranging from host defense to mitochondrial re-energization. |
| Databáze: | OpenAIRE |
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