Sphingosine-1-phosphate signaling in Leishmania donovani infection in macrophages
| Autor: | Shams Tabrez, Farha Naz, Abdur Rub, Mohd Arish, Mohammad Zulfazal Ahmad, Atahar Husein, Rahat Ali |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Leishmania Donovani Physiology Gene Expression Biochemistry White Blood Cells chemistry.chemical_compound 0302 clinical medicine Sphingosine Animal Cells Immune Physiology Medicine and Health Sciences Post-Translational Modification Phosphorylation Extracellular Signal-Regulated MAP Kinases S1PR2 Protozoans Leishmania S1PR3 Innate Immune System biology Chemistry lcsh:Public aspects of medicine Eukaryota Cell biology Receptors Lysosphingolipid Infectious Diseases Sphingosine kinase 1 030220 oncology & carcinogenesis Cytokines Cellular Types Research Article lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 Immune Cells p38 mitogen-activated protein kinases Immunology Leishmania donovani Cell Line 03 medical and health sciences parasitic diseases Parasitic Diseases Genetics Animals Sphingosine-1-phosphate Secretion Blood Cells Macrophages Organisms Public Health Environmental and Occupational Health Biology and Life Sciences Proteins lcsh:RA1-1270 Cell Biology Molecular Development biology.organism_classification Parasitic Protozoans 030104 developmental biology Gene Expression Regulation Immune System biology.protein Lysophospholipids Physiological Processes Developmental Biology |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 12, Iss 8, p e0006647 (2018) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | Background Sphingosine-1-phosphate (S1P) is a crucial regulator of a wide array of cellular processes, such as apoptosis, cell proliferation, migration, and differentiation, but its role in Leishmania donovani infection is unknown. Methodology/ principal findings In the present study, we observed that L. donovani infection in THP-1 derived macrophages (TDM) leads to decrease in the expression of S1pr2 and S1pr3 at mRNA level. We further observed that Leishmania infection inhibits the phosphorylation of sphingosine kinase 1 (sphK1) in a time-dependent manner. Exogenous S1P supplementation decreases L. donovani induced ERK1/2 phosphorylation and increases p38 phosphorylation in TDM, resulting in a decrease in the intracellular parasite burden in a dose-dependent manner. On the other hand, sphK inhibition by DMS increases ERK1/2 phosphorylation leading to increased IL-10 and parasite load. To gain further insight, cytokines expression were checked in S1P supplemented TDM and we observed increase in IL-12, while decrease IL-10 expression at mRNA and protein levels. In addition, treatment of antagonist of S1PR2 and S1PR3 such as JTE-013 and CAY10444 respectively enhanced Leishmania-induced ERK1/2 phosphorylation and parasite load. Conclusions Our overall study not only reports the significant role of S1P signaling during L. donovani infection but also provides a novel platform for the development of new drugs against Leishmaniasis. Author summary Leishmania donovani is an intracellular parasite which is internalized by host macrophages by subverting several intracellular signaling events. During infection suppression of p38 MAPK and activation of ERK1/2 MAPK have been acclaimed for survival and proliferation of these protozoan parasites. In this study, we show novel signaling pathways that interact with these MAPK that further contributes to determine the final fate of the disease. Sphingosine-1-Phosphate (S1P) is a bioactive lipid that binds to a family of G-protein coupled receptors known as S1P receptors. TDM infected with Leishmania donovani showed a decrease in the expression of S1PR1-3. Moreover, the enzyme that catalyzes S1P production, Sphingosine Kinase 1, showed decreased activation in a time-dependent fashion in infected cells. Furthermore, exogenously supplementation of S1P clears intracellular parasite burden by a decrease in ERK1/2 phosphorylation and IL-10 at mRNA and protein level. On the other hand, S1P induces anti-leishmanial response by activating p38 phosphorylation and IL-12 at mRNA as well as at protein level. To further gain insight on the receptors subtypes involved in the anti-leishmanial response, we specifically blocked S1PR2 and S1PR3. In this study, we found a tremendous increase in the parasite load as a result of increased IL-10 secretion and ERK1/2 phosphorylation on combination of these inhibitor doses. Taking together, our study thus suggested the possible involvement of S1PR2-3 during Leishmania donovani infection in human macrophages. These findings thus elaborate our knowledge in understanding the interaction of signaling intermediates during Leishmania infection which may lead to the discovery of novel therapeutic interventions. |
| Databáze: | OpenAIRE |
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