α-Lactosylceramide Protects Against iNKT-Mediated Murine Airway Hyperreactivity and Liver Injury Through Competitive Inhibition of Cd1d Binding
| Autor: | Hsien Neng Kao, Hsiao-Wu Hsieh, Christina Li-Ping Thio, Ya-Jen Chang, Alan Chuan Ying Lai, Jacquelyn Gervay-Hague, Yun Chiann Han, Po Yu Chi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Ceramide
medicine.medical_treatment chemical and pharmacologic phenomena 02 engineering and technology 010402 general chemistry CD1d 01 natural sciences lcsh:Chemistry Lactosylceramide chemistry.chemical_compound In vivo medicine 2.1 Biological and endogenous factors ConA Aetiology music Original Research Liver injury music.instrument biology Liver Disease T-cell receptor General Chemistry asthma 021001 nanoscience & nanotechnology medicine.disease 0104 chemical sciences 3. Good health Cell biology Chemistry Cytokine chemistry lcsh:QD1-999 CD1D biology.protein lipids (amino acids peptides and proteins) Digestive Diseases 0210 nano-technology Cell activation NKT cell glycolipid liver injury |
| Zdroj: | Frontiers in Chemistry, Vol 7 (2019) Frontiers in Chemistry |
| ISSN: | 2296-2646 |
| DOI: | 10.3389/fchem.2019.00811/full |
| Popis: | Invariant natural killer T (iNKT) cells, which are activated by T cell receptor (TCR)-dependent recognition of lipid-based antigens presented by the CD1d molecule, have been shown to participate in the pathogenesis of many diseases, including asthma and liver injury. Previous studies have shown the inhibition of iNKT cell activation using lipid antagonists can attenuate iNKT cell-induced disease pathogenesis. Hence, the development of iNKT cell-targeted glycolipids can facilitate the discovery of new therapeutics. In this study, we synthesized and evaluated α-lactosylceramide (α-LacCer), an α-galactosylceramide (α-GalCer) analog with lactose substitution for the galactose head and a shortened acyl chain in the ceramide tail, toward iNKT cell activation. We demonstrated that α-LacCer was a weak inducer for both mouse and human iNKT cell activation and cytokine production, and the iNKT induction by α-LacCer was CD1d-dependent. However, when co-administered with α-GalCer, α-LacCer inhibited α-GalCer-induced IL-4 and IFN-γ production from iNKT cells. Consequently, α-LacCer also ameliorated both α-GalCer and GSL-1-induced airway hyperreactivity and α-GalCer-induced neutrophilia when co-administered in vivo. Furthermore, we were able to inhibit the increases of ConA-induced AST, ALT and IFN-γ serum levels through α-LacCer pre-treatment, suggesting α-LacCer could protect against ConA-induced liver injury. Mechanistically, we discerned that α-LacCer suppressed α-GalCer-stimulated cytokine production through competing for CD1d binding. Since iNKT cells play a critical role in the development of AHR and liver injury, the inhibition of iNKT cell activation by α-LacCer present a possible new approach in treating iNKT cell-mediated diseases. |
| Databáze: | OpenAIRE |
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