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

Bazioti, Venetia; La Rose, Anouk M.; Maassen, Sjors; Bianchi, Frans; de Boer, Rinse; Halmos, Benedek; Dabral, Deepti; Guilbaud, Emma; Flohr-Svendsen, Arthur; Groenen, Anouk G.; Marmolejo-Garza, Alejandro; Koster, Mirjam H.; Kloosterhuis, Niels J.; Havinga, Rick; Pranger, Alle T.; Langelaar-Makkinje, Miriam; Bruin, Alain de; Sluis, Bart van de; Kohan, Alison B.; Yvan-Charvet, Laurent; Bogaart, Geert van den und Westerterp, Marit (2022): T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice. In: Nature Communications, Bd. 13, Nr. 1, 3799

Abstract

Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr(-/-) mice. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch