In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator
Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P<sub>1</sub>) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P<sub>1</sub> receptor modulators sequester circulating lymphocytes...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1191 |
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| author | Lisa Schlicher Paulina Kulig Audrey von Münchow Mark J. Murphy Marcel P. Keller |
| author_facet | Lisa Schlicher Paulina Kulig Audrey von Münchow Mark J. Murphy Marcel P. Keller |
| author_sort | Lisa Schlicher |
| collection | DOAJ |
| description | Cenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P<sub>1</sub>) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P<sub>1</sub> receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including T and B lymphocytes) in the bloodstream and inflamed tissues, making them an effective therapeutic concept for autoimmune disorders. Although the effect of S1P receptor modulators in reducing circulating lymphocytes is well documented, the precise molecular role of the S1P<sub>1</sub> receptor on these cell types is not fully understood. In this study, the mode of action of cenerimod on human primary lymphocytes in different activation states was investigated focusing on their chemotactic behavior towards S1P in real-time, concomitant to S1P<sub>1</sub> receptor expression and internalization dynamics. Here, we show that cenerimod effectively prevents T and B cell migration in a concentration-dependent manner. Interestingly, while T cell activation led to strong S1P<sub>1</sub> re-expression and enhanced migration; in B cells, an enhanced migration capacity and S1P<sub>1</sub> receptor surface expression was observed in an unstimulated state. Importantly, concomitant treatment with glucocorticoids (GCs), a frequently used treatment for autoimmune disorders, had no impact on the inhibitory activity of cenerimod on lymphocytes. |
| first_indexed | 2024-03-09T23:49:40Z |
| format | Article |
| id | doaj.art-5e0003de87c0406dbe3148ba6e50a5f4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:49:40Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5e0003de87c0406dbe3148ba6e50a5f42023-11-23T16:36:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233119110.3390/ijms23031191In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor ModulatorLisa Schlicher0Paulina Kulig1Audrey von Münchow2Mark J. Murphy3Marcel P. Keller4Idorsia Pharmaceuticals Ltd., 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd., 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd., 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd., 4123 Allschwil, SwitzerlandIdorsia Pharmaceuticals Ltd., 4123 Allschwil, SwitzerlandCenerimod is a potent, selective sphingosine 1-phosphate receptor 1 (S1P<sub>1</sub>) modulator currently investigated in a Phase IIb study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P<sub>1</sub> receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including T and B lymphocytes) in the bloodstream and inflamed tissues, making them an effective therapeutic concept for autoimmune disorders. Although the effect of S1P receptor modulators in reducing circulating lymphocytes is well documented, the precise molecular role of the S1P<sub>1</sub> receptor on these cell types is not fully understood. In this study, the mode of action of cenerimod on human primary lymphocytes in different activation states was investigated focusing on their chemotactic behavior towards S1P in real-time, concomitant to S1P<sub>1</sub> receptor expression and internalization dynamics. Here, we show that cenerimod effectively prevents T and B cell migration in a concentration-dependent manner. Interestingly, while T cell activation led to strong S1P<sub>1</sub> re-expression and enhanced migration; in B cells, an enhanced migration capacity and S1P<sub>1</sub> receptor surface expression was observed in an unstimulated state. Importantly, concomitant treatment with glucocorticoids (GCs), a frequently used treatment for autoimmune disorders, had no impact on the inhibitory activity of cenerimod on lymphocytes.https://www.mdpi.com/1422-0067/23/3/1191S1P<sub>1</sub> receptor modulatorlymphocytechemotaxisglucocorticoidssystemic lupus erythematosus (SLE) |
| spellingShingle | Lisa Schlicher Paulina Kulig Audrey von Münchow Mark J. Murphy Marcel P. Keller In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator International Journal of Molecular Sciences S1P<sub>1</sub> receptor modulator lymphocyte chemotaxis glucocorticoids systemic lupus erythematosus (SLE) |
| title | In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator |
| title_full | In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator |
| title_fullStr | In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator |
| title_full_unstemmed | In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator |
| title_short | In Vitro Characterization of Sphingosine 1-Phosphate Receptor 1 (S1P<sub>1</sub>) Expression and Mediated Migration of Primary Human T and B Cells in the Context of Cenerimod, a Novel, Selective S1P<sub>1</sub> Receptor Modulator |
| title_sort | in vitro characterization of sphingosine 1 phosphate receptor 1 s1p sub 1 sub expression and mediated migration of primary human t and b cells in the context of cenerimod a novel selective s1p sub 1 sub receptor modulator |
| topic | S1P<sub>1</sub> receptor modulator lymphocyte chemotaxis glucocorticoids systemic lupus erythematosus (SLE) |
| url | https://www.mdpi.com/1422-0067/23/3/1191 |
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