TY - JOUR
T1 - Hyperlipidaemia elicits an atypical, T helper 1-like CD4+T-cell response
T2 - A key role for very low-density lipoprotein
AU - van Os, Bram W.
AU - Vos, Winnie G.
AU - Bosmans, Laura A.
AU - van Tiel, Claudia M.
AU - Lith, Sanne C.
AU - den Toom, Myrthe S.
AU - Beckers, Linda
AU - Levels, Johannes H. M.
AU - van Wouw, Suzanne A. E.
AU - Zelcer, Noam
AU - Zaal, Esther A.
AU - Berkers, Celia R.
AU - van der Lest, Chris H. A.
AU - Helms, J. Bernd
AU - Weber, Christian
AU - Atzler, Dorothee
AU - de Winther, Menno P. J.
AU - Baardman, Jeroen
AU - Lutgens, Esther
N1 - Funding Information: This study was supported by the Deutsche Forschungsgemeinschaft (CRC 1123 to D.A., E.L., and C.W., DFG Einzelförderung 451372580 to D.A.). Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Aims: Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results: In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/-mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ(IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions: Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.
AB - Aims: Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results: In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/-mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ(IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions: Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.
KW - Hyperlipidaemia
KW - T cell inflammation
KW - VLDL
UR - http://www.scopus.com/inward/record.url?scp=85159593390&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/ehjopen/oead013
DO - https://doi.org/10.1093/ehjopen/oead013
M3 - Article
C2 - 36969380
SN - 2752-4191
VL - 3
JO - European heart journal open
JF - European heart journal open
IS - 2
M1 - oead013
ER -