T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Venetia Bazioti, Anouk M La Rose, Sjors Maassen, Frans Bianchi, Rinse de Boer, Benedek Halmos, Deepti Dabral, Emma Guilbaud, Arthur Flohr-Svendsen, Anouk G Groenen, Alejandro Marmolejo-Garza, Mirjam H Koster, Niels J Kloosterhuis, Rick Havinga, Alle T Pranger, Miriam Langelaar-Makkinje, Alain de Bruin, Bart van de Sluis, Alison B Kohan, Laurent Yvan-CharvetGeert van den Bogaart, Marit Westerterp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr -/-) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12-13 months) Ldlr -/- mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr -/- mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr -/- mice.

Original languageEnglish
Article number3799
Pages (from-to)1-23
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
This work is supported by VIDI (917.15.350) and Aspasia grants from the Netherlands Organization of Scientific Research (NWO) (M.W.), and a Rosalind Franklin Fellowship from the University of Groningen with EU Co-Fund attached (M.W.).

Publisher Copyright:
© 2022, The Author(s).

Fingerprint

Dive into the research topics of 'T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice'. Together they form a unique fingerprint.

Cite this