Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges
We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypert...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.930487/full |
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| author | Maha M. Itani Hala Jarrah Dina Maaliki Zeina Radwan Rima Farhat Hana A. Itani Hana A. Itani |
| author_facet | Maha M. Itani Hala Jarrah Dina Maaliki Zeina Radwan Rima Farhat Hana A. Itani Hana A. Itani |
| author_sort | Maha M. Itani |
| collection | DOAJ |
| description | We have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage. |
| first_indexed | 2024-04-11T21:26:37Z |
| format | Article |
| id | doaj.art-39365e68ec584953830c6d5a84444630 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T21:26:37Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-39365e68ec584953830c6d5a844446302022-12-22T04:02:22ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-09-011310.3389/fphys.2022.930487930487Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challengesMaha M. Itani0Hala Jarrah1Dina Maaliki2Zeina Radwan3Rima Farhat4Hana A. Itani5Hana A. Itani6Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDepartment of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, LebanonDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United StatesWe have previously shown that effector memory (TEM) cells accumulate in the bone marrow (BM) and the kidney in response to l-NAME/high salt challenge. It is not well understood if measures to block the exodus of that effector memory cells prevent redistribution of these cells and protect from hypertension-induced renal damage. We hypothesized that that effector memory cells that accumulate in the bone marrow respond to repeated salt challenges and can be reactivated and circulate to the kidney. Thus, to determine if mobilization of bone marrow that effector memory cells and secondary lymphoid organs contribute to the hypertensive response to delayed salt challenges, we employed fingolimod (FTY720), an S1PR1 functional antagonist by downregulating S1PR, which inhibits the egress of that effector memory cells used effectively in the treatment of multiple sclerosis and cardiovascular diseases. We exposed wild-type mice to the l-NAME for 2 weeks, followed by a wash-out period, a high salt diet feeding for 4 weeks, a wash-out period, and then a second high salt challenge with or without fingolimod. A striking finding is that that effector memory cell egress was dramatically attenuated from the bone marrow of mice treated with fingolimod with an associated reduction of renal that effector memory cells. Mice receiving fingolimod were protected from hypertension. We found that wild-type mice that received fingolimod during the second high salt challenge had a marked decrease in the renal damage markers. CD3+ T cell infiltration was significantly attenuated in the fingolimod-treated mice. To further examine the redistribution of bone marrow that effector memory cells in response to repeated hypertensive stimuli, we harvested the bone marrow from CD45.2 mice following the repeated high salt protocol with or without fingolimod; that effector memory cells were sorted and adoptively transferred (AT) to CD45.1 naïve recipients. Adoptively transferred that effector memory cells from mice treated with fingolimod failed to home to the bone marrow and traffic to the kidney in response to a high salt diet. We conclude that memory T cell mobilization contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension. Blocking the exodus of reactivated that effector memory cells from the bone marrow protects the kidney from hypertension-induced end-organ damage.https://www.frontiersin.org/articles/10.3389/fphys.2022.930487/fullinflammationmemory T cellsS1PR1memory T-lymphocytes traffickingkidneyhypertension |
| spellingShingle | Maha M. Itani Hala Jarrah Dina Maaliki Zeina Radwan Rima Farhat Hana A. Itani Hana A. Itani Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges Frontiers in Physiology inflammation memory T cells S1PR1 memory T-lymphocytes trafficking kidney hypertension |
| title | Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges |
| title_full | Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges |
| title_fullStr | Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges |
| title_full_unstemmed | Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges |
| title_short | Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges |
| title_sort | sphingosine 1 phosphate promotes hypertension specific memory t cell trafficking in response to repeated hypertensive challenges |
| topic | inflammation memory T cells S1PR1 memory T-lymphocytes trafficking kidney hypertension |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.930487/full |
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