TY - JOUR
T1 - T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
AU - Bazioti, Venetia
AU - La Rose, Anouk M
AU - Maassen, Sjors
AU - Bianchi, Frans
AU - de Boer, Rinse
AU - Halmos, Benedek
AU - Dabral, Deepti
AU - Guilbaud, Emma
AU - Flohr-Svendsen, Arthur
AU - Groenen, Anouk G
AU - Marmolejo-Garza, Alejandro
AU - Koster, Mirjam H
AU - Kloosterhuis, Niels J
AU - Havinga, Rick
AU - Pranger, Alle T
AU - Langelaar-Makkinje, Miriam
AU - de Bruin, Alain
AU - van de Sluis, Bart
AU - Kohan, Alison B
AU - Yvan-Charvet, Laurent
AU - van den Bogaart, Geert
AU - Westerterp, Marit
N1 - © 2022. The Author(s).
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Atherosclerosis/genetics
KW - Biological Transport
KW - Immunologic Deficiency Syndromes
KW - Inflammation
KW - Mice
KW - T-Lymphocytes
KW - Thymus Gland/abnormalities
U2 - 10.1038/s41467-022-31135-4
DO - 10.1038/s41467-022-31135-4
M3 - Article
C2 - 35778407
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3799
ER -