Wang Hua, Kc Pukar, Zhang Kaidi, Materne Clément, Lhomme Marie, Galier Sophie, Ichou Farid, Neves Carolina, Lehuen Agnès, Haas Joel T, Salem Joe-Elie, Guerin Maryse, Lesnik Philippe
Sorbonne Université, National Institute of Health and Medical Research (INSERM) U1166, Paris, France (H.W., P.K.C., K.Z., C.M., S.G., C.N., M.G., P.L.).
Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), ICAN OMICS, Paris, France (M.L., F.I.).
Circ Res. 2025 Apr 25;136(9):968-981. doi: 10.1161/CIRCRESAHA.124.325841. Epub 2025 Mar 26.
Previous clinical studies have indicated reduced circulating mucosal-associated invariant T (MAIT) cells in individuals with coronary artery disease. However, the precise role and underlying mechanisms of MAIT cells in this context remain unclear. Immune homeostasis plays a pivotal role in the development of atherosclerosis. This study explores the impact of MAIT cells on atherosclerosis.
Vα19 Ldlr mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1 (major histocompatibility complex-related molecule 1) Ldlr mice and their respective controls were used. Starting at 6 weeks of age, mice were subjected to a 1% cholesterol diet for 16 weeks. Additionally, the study analyzed circulating MAIT cell frequency and cholesterol levels in 68 patients with hypercholesterolemia.
In Vα19 Ldlr mice, increased MAIT cells demonstrated a protective effect against atherosclerosis by reducing VLDL-C (very-low-density lipoprotein cholesterol) levels through heightened cholesterol excretion. This effect was accompanied by elevated jejunal ABCB1a, ABCG5, and ABCG8 expression, mediated by augmented levels of Liver X receptor transcription and activation, likely through intestinal IL-22 (interleukin-22) signaling. Conversely, cholesterol reduction mediated by intestinal cholesterol excretion was blocked by inhibition of MAIT cells. Moreover, MAIT cell-deficient MR1 Ldlr mice exhibited elevated total cholesterol levels and increased atherosclerotic lesions. In patients with hypercholesterolemia, circulating MAIT cell frequency displayed negative correlations with VLDL-C levels and positive correlations with HDL-C (high-density lipoprotein cholesterol) levels.
Our findings demonstrate a new mechanism for plasma VLDL-C clearance by MAIT cell-mediated cholesterol excretion. The results provide further evidence that immunity is involved in cholesterol homeostasis. Targeting intestinal immunity to regulate cholesterol homeostasis holds promise as a new cholesterol-lowering modality to prevent atherosclerotic cardiovascular disease.
先前的临床研究表明，冠心病患者循环中的黏膜相关恒定T（MAIT）细胞减少。然而，MAIT细胞在此背景下的确切作用和潜在机制仍不清楚。免疫稳态在动脉粥样硬化的发展中起关键作用。本研究探讨MAIT细胞对动脉粥样硬化的影响。
使用MAIT细胞频率高的Vα19 Ldlr小鼠、MAIT细胞缺陷的MR1（主要组织相容性复合体相关分子1）Ldlr小鼠及其各自的对照。从6周龄开始，小鼠接受1%胆固醇饮食16周。此外，该研究分析了68例高胆固醇血症患者的循环MAIT细胞频率和胆固醇水平。
在Vα19 Ldlr小鼠中，MAIT细胞增多通过增强胆固醇排泄降低极低密度脂蛋白胆固醇（VLDL-C）水平，从而对动脉粥样硬化起到保护作用。这种作用伴随着空肠ABCB1a、ABCG5和ABCG8表达升高，这可能是由肝脏X受体转录和激活水平增加介导的，可能通过肠道白细胞介素-22（IL-22）信号传导。相反，MAIT细胞的抑制阻断了肠道胆固醇排泄介导的胆固醇降低。此外，MAIT细胞缺陷的MR1 Ldlr小鼠表现出总胆固醇水平升高和动脉粥样硬化病变增加。在高胆固醇血症患者中，循环MAIT细胞频率与VLDL-C水平呈负相关，与高密度脂蛋白胆固醇（HDL-C）水平呈正相关。
我们的研究结果揭示了MAIT细胞介导的胆固醇排泄清除血浆VLDL-C的新机制。这些结果进一步证明免疫参与胆固醇稳态。靶向肠道免疫以调节胆固醇稳态有望成为预防动脉粥样硬化性心血管疾病的一种新的降胆固醇方式。
