Hua Wang, Pukar K C, Kaidi Zhang, Clément Materne, Marie Lhomme, Sophie Galier, Farid Ichou, Carolina Neves, Agnes Lehuen, Joel T Haas, Joe-Elie Salem, Maryse Guerin, Philippe Lesnik
{"title":"MAIT细胞促进胆固醇排泄途径减轻动脉粥样硬化。","authors":"Hua Wang, Pukar K C, Kaidi Zhang, Clément Materne, Marie Lhomme, Sophie Galier, Farid Ichou, Carolina Neves, Agnes Lehuen, Joel T Haas, Joe-Elie Salem, Maryse Guerin, Philippe Lesnik","doi":"10.1161/CIRCRESAHA.124.325841","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Vα19<sup>+/-</sup> Ldlr<sup>-/-</sup> mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1<sup>-/-</sup> (major histocompatibility complex-related molecule 1) Ldlr<sup>-/-</sup> 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.</p><p><strong>Results: </strong>In Vα19<sup>+/-</sup> Ldlr<sup>-/-</sup> 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 LXR 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<sup>-/-</sup> Ldlr<sup>-/-</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"MAIT Cells Promote Cholesterol Excretion Pathways Mitigating Atherosclerosis.\",\"authors\":\"Hua Wang, Pukar K C, Kaidi Zhang, Clément Materne, Marie Lhomme, Sophie Galier, Farid Ichou, Carolina Neves, Agnes Lehuen, Joel T Haas, Joe-Elie Salem, Maryse Guerin, Philippe Lesnik\",\"doi\":\"10.1161/CIRCRESAHA.124.325841\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>Vα19<sup>+/-</sup> Ldlr<sup>-/-</sup> mice, characterized by a high MAIT cell frequency, and MAIT cell deficient MR1<sup>-/-</sup> (major histocompatibility complex-related molecule 1) Ldlr<sup>-/-</sup> 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.</p><p><strong>Results: </strong>In Vα19<sup>+/-</sup> Ldlr<sup>-/-</sup> 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 LXR 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<sup>-/-</sup> Ldlr<sup>-/-</sup> 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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10147,\"journal\":{\"name\":\"Circulation research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":16.5000,\"publicationDate\":\"2025-03-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.124.325841\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.124.325841","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Background: 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.
Methods: 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.
Results: 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 LXR 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.
Conclusions: 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.
期刊介绍：
Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies.
Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities.
In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field.
Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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