William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, School of Health Sciences, The University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester M13 9PT, UK.
Cardiovasc Res. 2020 Apr 1;116(5):1006-1020. doi: 10.1093/cvr/cvz208.
Adaptive immunity contributes to the pathogenesis of cardiovascular metabolic disorders (CVMD). The omega-3 polyunsaturated fatty acids (n-3PUFA) are beneficial for cardiovascular health, with potential to improve the dysregulated adaptive immune responses associated with metabolic imbalance. We aimed to explore the mechanisms through which n-3PUFA may alter T cell motility and tissue distribution to promote a less inflammatory environment and improve lymphocyte function in CVMD.
Using mass spectrometry lipidomics, cellular, biochemical, and in vivo and ex vivo analyses, we investigated how eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the main n-3PUFA, modify the trafficking patterns of activated CD4+ T cells. In mice subjected to allogeneic immunization, a 3-week n-3PUFA-enriched diet reduced the number of effector memory CD4+ T cells found in adipose tissue, and changed the profiles of eicosanoids, octadecanoids, docosanoids, endocannabinoids, 2-monoacylglycerols, N-acyl ethanolamines, and ceramides, in plasma, lymphoid organs, and fat tissues. These bioactive lipids exhibited differing chemotactic properties when tested in chemotaxis assays with activated CD4+ T cells in vitro. Furthermore, CD4+ T cells treated with EPA and DHA showed a significant reduction in chemokinesis, as assessed by trans-endothelial migration assays, and, when implanted in recipient mice, demonstrated less efficient migration to the inflamed peritoneum. Finally, EPA and DHA treatments reduced the number of polarized CD4+ T cells in vitro, altered the phospholipid composition of membrane microdomains and decreased the activity of small Rho GTPases, Rhoα, and Rac1 instrumental in cytoskeletal dynamics.
Our findings suggest that EPA and DHA affect the motility of CD4+ T cells and modify their ability to reach target tissues by interfering with the cytoskeletal rearrangements required for cell migration. This can explain, at least in part, the anti-inflammatory effects of n-3PUFA supporting their potential use in interventions aiming to address adipocyte low-grade inflammation associated with cardiovascular metabolic disease.
适应性免疫有助于心血管代谢紊乱（CVMD）的发病机制。ω-3 多不饱和脂肪酸（n-3PUFA）有益于心血管健康，具有改善与代谢失衡相关的失调适应性免疫反应的潜力。我们旨在探索 n-3PUFA 可能改变 T 细胞迁移和组织分布的机制，以促进较少炎症环境并改善 CVMD 中的淋巴细胞功能。
使用质谱脂质组学、细胞、生化以及体内和体外分析，我们研究了二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）（主要的 n-3PUFA）如何改变激活的 CD4+T 细胞的迁移模式。在接受同种免疫的小鼠中，富含 n-3PUFA 的饮食 3 周可减少脂肪组织中效应记忆 CD4+T 细胞的数量，并改变血浆、淋巴器官和脂肪组织中类二十烷酸、十八烷酸、二十二烷酸、内源性大麻素、2-单酰甘油、N-酰基乙醇胺和神经酰胺的谱。在体外用激活的 CD4+T 细胞进行趋化性测定时，这些生物活性脂质表现出不同的趋化特性。此外，用 EPA 和 DHA 处理的 CD4+T 细胞在跨内皮迁移测定中显示出趋化性显著降低，并且当植入受体小鼠时，向炎症性腹膜的迁移效率较低。最后，EPA 和 DHA 处理减少了体外极化 CD4+T 细胞的数量，改变了质膜微区的磷脂组成，并降低了细胞骨架动态所必需的小 Rho GTPase、Rhoα和 Rac1 的活性。
我们的研究结果表明，EPA 和 DHA 通过干扰细胞迁移所需的细胞骨架重排来影响 CD4+T 细胞的迁移，并改变其到达靶组织的能力。这至少可以部分解释 n-3PUFA 的抗炎作用，支持它们在旨在解决与心血管代谢疾病相关的脂肪细胞低度炎症的干预措施中的潜在用途。
