Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells
Sphingosine-1 phosphate receptor 1 (S1PR1) is expressed by lymphocytes and regulates their egress from secondary lymphoid organs. Innate lymphoid cell (ILC) family has been expanded with the discovery of group 1, 2 and 3 ILCs, namely ILC1, ILC2 and ILC3. ILC3 and ILC1 have remarkable similarity to C...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2019-02-01
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Series: | Frontiers in Immunology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00217/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ahmet Eken Ahmet Eken Mehmet Fatih Yetkin Alperen Vural Fatma Zehra Okus Fatma Zehra Okus Serife Erdem Serife Erdem Zehra Busra Azizoglu Zehra Busra Azizoglu Yesim Haliloglu Yesim Haliloglu Mustafa Cakir Mustafa Cakir Enes Mehmet Turkoglu Omer Kilic Irfan Kara Hamiyet Dönmez Altuntaş Mohamed Oukka Mehmet Serdar Kutuk Meral Mirza Halit Canatan Halit Canatan |
spellingShingle |
Ahmet Eken Ahmet Eken Mehmet Fatih Yetkin Alperen Vural Fatma Zehra Okus Fatma Zehra Okus Serife Erdem Serife Erdem Zehra Busra Azizoglu Zehra Busra Azizoglu Yesim Haliloglu Yesim Haliloglu Mustafa Cakir Mustafa Cakir Enes Mehmet Turkoglu Omer Kilic Irfan Kara Hamiyet Dönmez Altuntaş Mohamed Oukka Mehmet Serdar Kutuk Meral Mirza Halit Canatan Halit Canatan Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells Frontiers in Immunology S1PR1 ILC3 ILC1 Fingolimod FTY720 SEW2871 |
author_facet |
Ahmet Eken Ahmet Eken Mehmet Fatih Yetkin Alperen Vural Fatma Zehra Okus Fatma Zehra Okus Serife Erdem Serife Erdem Zehra Busra Azizoglu Zehra Busra Azizoglu Yesim Haliloglu Yesim Haliloglu Mustafa Cakir Mustafa Cakir Enes Mehmet Turkoglu Omer Kilic Irfan Kara Hamiyet Dönmez Altuntaş Mohamed Oukka Mehmet Serdar Kutuk Meral Mirza Halit Canatan Halit Canatan |
author_sort |
Ahmet Eken |
title |
Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells |
title_short |
Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells |
title_full |
Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells |
title_fullStr |
Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells |
title_full_unstemmed |
Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells |
title_sort |
fingolimod alters tissue distribution and cytokine production of human and murine innate lymphoid cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2019-02-01 |
description |
Sphingosine-1 phosphate receptor 1 (S1PR1) is expressed by lymphocytes and regulates their egress from secondary lymphoid organs. Innate lymphoid cell (ILC) family has been expanded with the discovery of group 1, 2 and 3 ILCs, namely ILC1, ILC2 and ILC3. ILC3 and ILC1 have remarkable similarity to CD4+ helper T cell lineage members Th17 and Th1, respectively, which are important in the pathology of multiple sclerosis (MS). Whether human ILC subsets express S1PR1 or respond to its ligands have not been studied. In this study, we used peripheral blood/cord blood and tonsil lymphocytes as a source of human ILCs. We show that human ILCs express S1PR1 mRNA and protein and migrate toward S1P receptor ligands. Comparison of peripheral blood ILC numbers between fingolimod-receiving and treatment-free MS patients revealed that, in vivo, ILCs respond to fingolimod, an S1PR1 agonist, resulting in ILC-penia in circulation. Similarly, murine ILCs responded to fingolimod by exiting blood and accumulating in the secondary lymph nodes. Importantly, ex vivo exposure of ILC3 and ILC1 to fingolimod or SEW2871, another S1PR1 antagonist, reduced production of ILC3- and ILC1- associated cytokines GM-CSF, IL-22, IL-17, and IFN-γ, respectively. Surprisingly, despite reduced number of lamina propria-resident ILC3s in the long-term fingolimod-treated mice, ILC3-associated IL-22, IL-17A, GM-CSF and antimicrobial peptides were high in the gut compared to controls, suggesting that its long term use may not compromise mucosal barrier function. To our knowledge, this is the first study to investigate the impact of fingolimod on human ILC subsets in vivo and ex vivo, and provides insight into the impact of long term fingolimod use on ILC populations. |
topic |
S1PR1 ILC3 ILC1 Fingolimod FTY720 SEW2871 |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.00217/full |
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doaj-fc96ace1d193452aa918ace4f054fb312020-11-25T00:44:48ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-02-011010.3389/fimmu.2019.00217429611Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid CellsAhmet Eken0Ahmet Eken1Mehmet Fatih Yetkin2Alperen Vural3Fatma Zehra Okus4Fatma Zehra Okus5Serife Erdem6Serife Erdem7Zehra Busra Azizoglu8Zehra Busra Azizoglu9Yesim Haliloglu10Yesim Haliloglu11Mustafa Cakir12Mustafa Cakir13Enes Mehmet Turkoglu14Omer Kilic15Irfan Kara16Hamiyet Dönmez Altuntaş17Mohamed Oukka18Mehmet Serdar Kutuk19Meral Mirza20Halit Canatan21Halit Canatan22Erciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyDepartment of Neurology, Erciyes University School of Medicine, Kayseri, TurkeyDepartment of Ear Nose and Throat, Erciyes University School of Medicine, Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeyDepartment of Ear Nose and Throat, Erciyes University School of Medicine, Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyDepartment of Immunology, University of Washington, Seattle, WA, United StatesDepartment of Obstetrics and Gynecology, Erciyes University School of Medicine, Kayseri, TurkeyDepartment of Neurology, Erciyes University School of Medicine, Kayseri, TurkeyErciyes University School of Medicine, Department of Medical Biology, Kayseri, TurkeyBetül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, TurkeySphingosine-1 phosphate receptor 1 (S1PR1) is expressed by lymphocytes and regulates their egress from secondary lymphoid organs. Innate lymphoid cell (ILC) family has been expanded with the discovery of group 1, 2 and 3 ILCs, namely ILC1, ILC2 and ILC3. ILC3 and ILC1 have remarkable similarity to CD4+ helper T cell lineage members Th17 and Th1, respectively, which are important in the pathology of multiple sclerosis (MS). Whether human ILC subsets express S1PR1 or respond to its ligands have not been studied. In this study, we used peripheral blood/cord blood and tonsil lymphocytes as a source of human ILCs. We show that human ILCs express S1PR1 mRNA and protein and migrate toward S1P receptor ligands. Comparison of peripheral blood ILC numbers between fingolimod-receiving and treatment-free MS patients revealed that, in vivo, ILCs respond to fingolimod, an S1PR1 agonist, resulting in ILC-penia in circulation. Similarly, murine ILCs responded to fingolimod by exiting blood and accumulating in the secondary lymph nodes. Importantly, ex vivo exposure of ILC3 and ILC1 to fingolimod or SEW2871, another S1PR1 antagonist, reduced production of ILC3- and ILC1- associated cytokines GM-CSF, IL-22, IL-17, and IFN-γ, respectively. Surprisingly, despite reduced number of lamina propria-resident ILC3s in the long-term fingolimod-treated mice, ILC3-associated IL-22, IL-17A, GM-CSF and antimicrobial peptides were high in the gut compared to controls, suggesting that its long term use may not compromise mucosal barrier function. To our knowledge, this is the first study to investigate the impact of fingolimod on human ILC subsets in vivo and ex vivo, and provides insight into the impact of long term fingolimod use on ILC populations.https://www.frontiersin.org/article/10.3389/fimmu.2019.00217/fullS1PR1ILC3ILC1FingolimodFTY720SEW2871 |