Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors
© 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH..
Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APCmin/+ mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
European journal of immunology - 51(2021), 9 vom: 01. Sept., Seite 2317-2329 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Akeus, Paulina [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.11.2021 Date Revised 16.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/eji.202149208 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328182583 |
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| 100 | 1 | |a Akeus, Paulina |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 16.11.2021 | ||
| 500 | |a Date Revised 16.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. | ||
| 520 | |a Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APCmin/+ mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CXCL10 | |
| 650 | 4 | |a VCAM-1 | |
| 650 | 4 | |a endothelial cell | |
| 650 | 4 | |a nSMase2 | |
| 650 | 4 | |a regulatory T cells | |
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| 650 | 7 | |a Sphingomyelin Phosphodiesterase |2 NLM | |
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| 700 | 1 | |a Szeponik, Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Langenes, Veronica |e verfasserin |4 aut | |
| 700 | 1 | |a Karlsson, Viktoria |e verfasserin |4 aut | |
| 700 | 1 | |a Sundström, Patrik |e verfasserin |4 aut | |
| 700 | 1 | |a Bexe-Lindskog, Elinor |e verfasserin |4 aut | |
| 700 | 1 | |a Tallon, Carolyn |e verfasserin |4 aut | |
| 700 | 1 | |a Slusher, Barbara S |e verfasserin |4 aut | |
| 700 | 1 | |a Quiding-Järbrink, Marianne |e verfasserin |4 aut | |
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