AIMS 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. METHODS AND RESULTS 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 polarised 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. CONCLUSIONS 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.

中文翻译：

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Omega-3多不饱和脂肪酸通过直接和脂质介体依赖性作用，影响CD4 + T细胞运动性和脂肪组织分布。

AIMS适应性免疫有助于心血管代谢紊乱（CVMD）的发病。ω-3多不饱和脂肪酸（n-3PUFA）对心血管健康有益，并具有改善与代谢不平衡相关的适应性免疫反应失调的潜力。我们旨在探讨n-3PUFA通过改变T细胞运动性和组织分布来促进炎症性环境减少并改善CVMD中淋巴细胞功能的机制。方法和结果使用质谱脂质组学，细胞，生化以及体内和离体分析，我们研究了主要的n-3PUFA二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）如何改变活化的CD4 + T细胞的运输模式。在接受同种异体免疫的小鼠中，3周的富含n-3PUFA的饮食减少了在脂肪组织中发现的效应记忆CD4 + T细胞的数量，并改变了血浆中类花生酸，十八烷类，二十烷类，内源性大麻素，2-单酰基甘油，N-酰基乙醇胺和神经酰胺的分布，淋巴器官和脂肪组织。当在体外用活化的CD4 + T细胞进行趋化性检测时，这些生物活性脂质表现出不同的趋化性质。此外，经跨内皮迁移分析评估，经EPA和DHA处理的CD4 + T细胞显示出明显的趋化因子降低，并且当植入受体小鼠体内时，向炎症性腹膜的迁移效率较低。最后，EPA和DHA处理可减少体外极化CD4 + T细胞的数量，改变了膜微区的磷脂组成，并降低了在细胞骨架动力学中起作用的小Rho GTPases，Rhoα和Rac1的活性。结论我们的发现表明EPA和DHA通过干扰细胞迁移所需的细胞骨架重排，影响CD4 + T细胞的运动并改变其到达靶组织的能力。这可以至少部分解释n-3PUFA的抗炎作用，支持其在旨在解决与心血管代谢疾病有关的脂肪细胞低度炎症的干预措施中的潜在用途。结论我们的发现表明EPA和DHA通过干扰细胞迁移所需的细胞骨架重排，影响CD4 + T细胞的运动并改变其到达靶组织的能力。这可以至少部分解释n-3PUFA的抗炎作用，支持其在旨在解决与心血管代谢疾病有关的脂肪细胞低度炎症的干预措施中的潜在用途。结论我们的发现表明EPA和DHA通过干扰细胞迁移所需的细胞骨架重排，影响CD4 + T细胞的运动并改变其到达靶组织的能力。这可以至少部分解释n-3PUFA的抗炎作用，支持其在旨在解决与心血管代谢疾病有关的脂肪细胞低度炎症的干预措施中的潜在用途。