Sphingosine 1 phosphate promotes hypertension specific memory T cell trafficking in response to repeated hypertensive challenges

Abstract

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.

Dietary High Salt Intake Exacerbates SGK1-Mediated T Cell Pathogenicity in L-NAME/High Salt-Induced Hypertension

“…The kidney is essential in hypertension immunology [43][44][45]. Renal denervation prevents the accumulation of T cells in the kidneys and the subsequent inflammatory response [43].…”

“…Thoracic aortas were excised, cleared of perivascular adipose tissue, minced, and enzymatically digested at 37 • C for 30 min using a digestion cocktail of collagenase types A and B (Roche Diagnostics, Mannheim, Germany) in RPMI 1640, with rotation in a hybridization oven. After digestion, the cells were centrifuged at 800× g for 5 min, resuspended in PBS, and strained through a 70 µm cell strainer (Falcon, BD Biosciences, Franklin Lakes, NJ, USA) to remove undigested tissue and debris [45].…”

Targeting inflammation in hypertension

“…Mice treated with the S1PR inhibitor could not sustain hypertension compared to untreated mice. Hereby the authors demonstrate that repeated hypertensive stimuli lead to mobilization of memory T-cells from bone marrow, which may contribute to predisposition to hypertension and target organ damage [30 ▪ ].…”

“…Besides classical effector CD4 + and CD8 + T-cells, which mediate hypertensive organ damage, memory T-cells are also a source of IL-17 and INF-γ, triggering elevation in blood pressure after repeated hypertensive stimuli [28,29]. Itani et al [30 ▪ ] critically addressed the role of these memory T-cells by using fingolimod, which antagonizes Sphingosine-1-phosphate receptor (S1PR). By inhibiting S1PR, egress of effector memory T-cells from bone marrow was attenuated and mice were protected from hypertensive kidney injury.…”

Editorial: Inflammation in hypertensive disorders

“…The migration of T cells from lymphoid organs to the circulation depends on the interaction between the chemoattractant sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors one and 2 (S1PR1+2). FTY720 is a functional agonist of S1PR1 that prevents the egression of lymphocytes from secondary lymphoid organs to the circulation ( Matloubian et al, 2004 ; Garris et al, 2014 ; Itani et al, 2022 ).…”