Inflammatory role of extracellular sphingolipids in Cystic Fibrosis.

Abstract

Ceramide is emerging as one of the players of inflammation in lung diseases. However, data on its inflammatory role in Cystic Fibrosis (CF) as part of the extracellular machinery driven by lung mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) are missing. We obtained an in vitro model of CF-MSC by treating control human lung MSCs with a specific CFTR inhibitor. We characterized EVs populations derived from MSCs (ctr EVs) and CF-MSCs (CF-EVs) and analyzed their sphingolipid profile by LC-MS/MS. To evaluate their immunomodulatory function, we treated an in vitro human model of CF, with both EVs populations. Our data show that the two EVs populations differ for the average size, amount, and rate of uptake. CF-EVs display higher ceramide and dihydroceramide accumulation as compared to control EVs, suggesting the involvement of the de novo biosynthesis pathway in the parental CF-MSCs. Higher sphingomyelinase activity in CF-MSCs, driven by inflammation-induced ceramide accumulation, sustains the exocytosis of vesicles that export new formed pro-inflammatory ceramide. Our results suggest that CFTR dysfunction associates with an enhanced sphingolipid metabolism leading to the release of EVs that export the excess of pro-inflammatory Cer to the recipient cells, thus contributing to maintain the unresolved inflammatory status of CF.

• Authors: Aida Zulueta, Valeria Peli, Michele Dei Cas, Michela Colombo, Rita Paroni, Monica Falleni, Alessandro Baisi, Valentina Bollati, Raffaella Chiaramonte, Elena Del Favero, Riccardo Ghidoni, Anna Caretti
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 116 Pg. 105622 (11 2019) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 31563560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• CFTR protein, human
• Ceramides
• Thiazolidines
• dihydroceramide
• Cystic Fibrosis Transmembrane Conductance Regulator
• Sphingomyelin Phosphodiesterase

Topics

• Ceramides (metabolism, pharmacology)
• Cystic Fibrosis (genetics, metabolism, pathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (antagonists & inhibitors, genetics, metabolism)
• Exocytosis
• Extracellular Vesicles (chemistry, metabolism)
• Gene Expression
• Humans
• Inflammation
• Lung (metabolism, pathology)
• Mesenchymal Stem Cells (drug effects, metabolism, pathology)
• Models, Biological
• Primary Cell Culture
• Sphingomyelin Phosphodiesterase (genetics, metabolism)
• Thiazolidines (pharmacology)