S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation
BackgroundSphingosine-1-phosphate (S1P) and its five receptors S1PR1-5 play an essential role in the migration, differentiation and activation of various immune cells. Several S1PR modulators with distinct selectivity have been recently approved for the treatment of various inflammatory diseases. Am...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1590816/full |
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| author | Fiona K. Sailer Megan A. Palmer Blerina Aliraj Jan Heering Jan Heering Andreas Brockmann Mohammed A. F. Elewa Mohammed A. F. Elewa Aissa Röhrig Aissa Röhrig Ewgenij Proschak Ewgenij Proschak Ewgenij Proschak Dariusz T. Stepniak Simeon Ramsey Bernhard Brüne Bernhard Brüne Andreas Weigert |
| author_facet | Fiona K. Sailer Megan A. Palmer Blerina Aliraj Jan Heering Jan Heering Andreas Brockmann Mohammed A. F. Elewa Mohammed A. F. Elewa Aissa Röhrig Aissa Röhrig Ewgenij Proschak Ewgenij Proschak Ewgenij Proschak Dariusz T. Stepniak Simeon Ramsey Bernhard Brüne Bernhard Brüne Andreas Weigert |
| author_sort | Fiona K. Sailer |
| collection | DOAJ |
| description | BackgroundSphingosine-1-phosphate (S1P) and its five receptors S1PR1-5 play an essential role in the migration, differentiation and activation of various immune cells. Several S1PR modulators with distinct selectivity have been recently approved for the treatment of various inflammatory diseases. Among those are Ozanimod, an S1PR1/5 modulator approved for the treatment of ulcerative colitis and multiple sclerosis, and Etrasimod, an S1PR1/4/5 modulator approved for the treatment of ulcerative colitis. Chronic autoinflammatory diseases such as the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis are characterized by an abundance of disease-propagating immune cells in the gastrointestinal tract. Since currently available treatment options such as biologics provide a sometimes inadequate treatment response, one alternative strategy to treat IBDs is the use of S1P receptor modulators.ObjectiveWe aimed to investigate if targeting S1PR4 affects the impact of Etrasimod on the activation of primary human immune cells, and to elucidate the mode of action of Etrasimod on S1PR4.MethodsPrimary human macrophages, plasmacytoid dendritic cells and neutrophils were pretreated with S1P, Etrasimod (S1PR1/4/5), Ozanimod (S1PR1/5), Siponimod (S1PR1/5), CYM 50308 (S1PR4 agonist) and CYM 50358 (S1PR4 antagonist), and then stimulated with Zymosan A, ODN 2336 and PMA, respectively. We measured cytokine and chemokine production by macrophages and plasmacytoid dendritic cells via CBA/Legendplex, and survival and activation markers for neutrophils via flow cytometry. Confocal microscopy of S1PR-expressing CHO-K1 cell lines was used to study receptor internalization.ResultsWe found that signaling induced by S1P, Etrasimod and the S1PR4 agonist attenuates CCL20 and CXCL5 production by Zymosan-stimulated macrophages, and these findings were confirmed by S1PR4 knockdown. Additionally, S1PR4 was involved in the regulation of IFN-α production by ODN2336-stimulated plasmacytoid dendritic cells. Lastly, both Etrasimod and the S1PR4 agonist reduced the activation level of PMA-stimulated neutrophils. Regarding receptor dynamics, we show that Etrasimod induces internalization of S1PR4.ConclusionTaken together, our data show that S1PR4 takes on an essential role in the regulation of various immunological functions, and that Etrasimod can act as a superagonist/functional antagonist of S1PR4. |
| format | Article |
| id | doaj-art-7f1c759495124bd2a59f1233b9a62fd6 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-7f1c759495124bd2a59f1233b9a62fd62025-08-20T03:15:04ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-04-011610.3389/fphar.2025.15908161590816S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activationFiona K. Sailer0Megan A. Palmer1Blerina Aliraj2Jan Heering3Jan Heering4Andreas Brockmann5Mohammed A. F. Elewa6Mohammed A. F. Elewa7Aissa Röhrig8Aissa Röhrig9Ewgenij Proschak10Ewgenij Proschak11Ewgenij Proschak12Dariusz T. Stepniak13Simeon Ramsey14Bernhard Brüne15Bernhard Brüne16Andreas Weigert17Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, GermanyFraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Frankfurt am Main, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, GermanyInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyBiochemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, EgyptInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyDepartment of Internal Medicine 1, Goethe University Hospital, Frankfurt am Main, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, GermanyFraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Frankfurt am Main, GermanyInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt am Main, GermanyArena Pharmaceuticals, Pfizer Inc., New York, NY, United StatesInflammation and Immunology, Pfizer Inc., Cambridge, MA, United StatesInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyFrankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt am Main, GermanyInstitute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, GermanyBackgroundSphingosine-1-phosphate (S1P) and its five receptors S1PR1-5 play an essential role in the migration, differentiation and activation of various immune cells. Several S1PR modulators with distinct selectivity have been recently approved for the treatment of various inflammatory diseases. Among those are Ozanimod, an S1PR1/5 modulator approved for the treatment of ulcerative colitis and multiple sclerosis, and Etrasimod, an S1PR1/4/5 modulator approved for the treatment of ulcerative colitis. Chronic autoinflammatory diseases such as the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis are characterized by an abundance of disease-propagating immune cells in the gastrointestinal tract. Since currently available treatment options such as biologics provide a sometimes inadequate treatment response, one alternative strategy to treat IBDs is the use of S1P receptor modulators.ObjectiveWe aimed to investigate if targeting S1PR4 affects the impact of Etrasimod on the activation of primary human immune cells, and to elucidate the mode of action of Etrasimod on S1PR4.MethodsPrimary human macrophages, plasmacytoid dendritic cells and neutrophils were pretreated with S1P, Etrasimod (S1PR1/4/5), Ozanimod (S1PR1/5), Siponimod (S1PR1/5), CYM 50308 (S1PR4 agonist) and CYM 50358 (S1PR4 antagonist), and then stimulated with Zymosan A, ODN 2336 and PMA, respectively. We measured cytokine and chemokine production by macrophages and plasmacytoid dendritic cells via CBA/Legendplex, and survival and activation markers for neutrophils via flow cytometry. Confocal microscopy of S1PR-expressing CHO-K1 cell lines was used to study receptor internalization.ResultsWe found that signaling induced by S1P, Etrasimod and the S1PR4 agonist attenuates CCL20 and CXCL5 production by Zymosan-stimulated macrophages, and these findings were confirmed by S1PR4 knockdown. Additionally, S1PR4 was involved in the regulation of IFN-α production by ODN2336-stimulated plasmacytoid dendritic cells. Lastly, both Etrasimod and the S1PR4 agonist reduced the activation level of PMA-stimulated neutrophils. Regarding receptor dynamics, we show that Etrasimod induces internalization of S1PR4.ConclusionTaken together, our data show that S1PR4 takes on an essential role in the regulation of various immunological functions, and that Etrasimod can act as a superagonist/functional antagonist of S1PR4.https://www.frontiersin.org/articles/10.3389/fphar.2025.1590816/fullSphingosine-1-phosphateS1P receptor modulatorS1PR4Etrasimodinflammatory bowel disease |
| spellingShingle | Fiona K. Sailer Megan A. Palmer Blerina Aliraj Jan Heering Jan Heering Andreas Brockmann Mohammed A. F. Elewa Mohammed A. F. Elewa Aissa Röhrig Aissa Röhrig Ewgenij Proschak Ewgenij Proschak Ewgenij Proschak Dariusz T. Stepniak Simeon Ramsey Bernhard Brüne Bernhard Brüne Andreas Weigert S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation Frontiers in Pharmacology Sphingosine-1-phosphate S1P receptor modulator S1PR4 Etrasimod inflammatory bowel disease |
| title | S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation |
| title_full | S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation |
| title_fullStr | S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation |
| title_full_unstemmed | S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation |
| title_short | S1PR4-dependent effects of Etrasimod on primary human myeloid immune cell activation |
| title_sort | s1pr4 dependent effects of etrasimod on primary human myeloid immune cell activation |
| topic | Sphingosine-1-phosphate S1P receptor modulator S1PR4 Etrasimod inflammatory bowel disease |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1590816/full |
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