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Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

ABSTRACT: The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC.

SUBMITTER: Staquicini DI

PROVIDER: S-EPMC10450669 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

Staquicini Daniela I DI Cardó-Vila Marina M Rotolo Jimmy A JA Staquicini Fernanda I FI Tang Fenny H F FHF Smith Tracey L TL Ganju Aditya A Schiavone Carmine C Dogra Prashant P Wang Zhihui Z Cristini Vittorio V Giordano Ricardo J RJ Ozawa Michael G MG Driessen Wouter H P WHP Proneth Bettina B Souza Glauco R GR Brinker Lina M LM Noureddine Achraf A Snider Ashley J AJ Canals Daniel D Gelovani Juri G JG Petrache Irina I Tuder Rubin M RM Obeid Lina M LM Hannun Yusuf A YA Kolesnick Richard N RN Brinker C Jeffrey CJ Pasqualini Renata R Arap Wadih W

Proceedings of the National Academy of Sciences of the United States of America 20230814 34

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platfor ...[more]

PMID: 37579172

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Project description:BackgroundParticulate air pollution in lung epithelial cells induces pathogenic endpoints like proliferation, apoptosis, and pro-inflammatory reactions. The activation of the epidermal growth factor receptor (EGFR) is a key event responsible for signalling events involving mitogen activated protein kinases specific for these endpoints. The molecular events leading to receptor activation however are not well understood. These events are relevant for the toxicological evaluation of inhalable particles as well as for potential preventive strategies in situations when particulate air pollution cannot be avoided. The current study therefore had the objective to elucidate membrane-coupled events leading to EGFR activation and the subsequent signalling cascade in lung epithelial cells. Furthermore, we aimed to identify the molecular target of ectoine, a biophysical active substance which we described to prevent carbon nanoparticle-induced lung inflammation.MethodsMembrane signalling events were investigated in isolated lipid rafts from lung epithelial cells with regard to lipid and protein content of the signalling platforms. Using positive and negative intervention approaches, lipid raft changes, subsequent signalling events, and lung inflammation were investigated in vitro in lung epithelial cells (RLE-6TN) and in vivo in exposed animals.ResultsCarbon nanoparticle treatment specifically led to an accumulation of ceramides in lipid rafts. Detailed analyses demonstrated a causal link of ceramides and subsequent EGFR activation coupled with a loss of the receptor in the lipid raft fractions. In vitro and in vivo investigations demonstrate the relevance of these events for carbon nanoparticle-induced lung inflammation. Moreover, the compatible solute ectoine was able to prevent ceramide-mediated EGFR phosphorylation and subsequent signalling as well as lung inflammation in vivo.ConclusionThe data identify a so far unknown event in pro-inflammatory signalling and contribute to the understanding of particle cell interaction and therefore to risk identification and risk assessment of inhalable xenobiotics. Moreover, as this cellular reaction can be prevented by the well tolerated substance ectoine, a molecular preventive strategy for susceptible persons against airway inflammation is proposed.

Dataset Information

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

Publications

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

Similar Datasets

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