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Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells
A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T
(Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell
migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell
migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been
shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia
contributes to altered migration of Treg cells, in part, by affecting cellular metabolism.
Dyslipidemia was induced by feeding Ldlr-/- mice a Western-type diet for 16-20
weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined.
Dyslipidemia was associated with altered mTORC2 signaling in Treg cells, decreased expression of
membrane proteins involved in migration, including CD62L, CCR7 and S1Pr1, and...
Show moreA hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T
(Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell
migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell
migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been
shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia
contributes to altered migration of Treg cells, in part, by affecting cellular metabolism.
Dyslipidemia was induced by feeding Ldlr-/- mice a Western-type diet for 16-20
weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined.
Dyslipidemia was associated with altered mTORC2 signaling in Treg cells, decreased expression of
membrane proteins involved in migration, including CD62L, CCR7 and S1Pr1, and decreased Treg
cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia
inhibited mTORC1 signaling, induced PPARδ activation and increased fatty acid (FA) oxidation in
Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with normolipidemia or
dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a
synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA
oxidation dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell
migration into the inflamed peritoneum and into atherosclerotic lesions in vitro.
Altogether, our findings implicate that dyslipidemia does not contribute to
atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like
migratory phenotype in Treg cells.
- All authors
- Amersfoort, J.; Schaftenaar, F.H.; Douna, H.; Santbrink, P.J. van; Puijvelde, G.H.M. van; Slütter, B.; Foks, A.C.; Harms, A.; Moreno-Gordaliza, E.; Wang, Y.; Hankemeier, T.; Bot, I.; Chi, H.; Kuiper, J.
- Date
- 2020-07-11
- Journal
- Cardiovascular research
- Volume
- 117
- Issue
- 5
- Pages
- 1309 - 1324