Omega-3 polyunsaturated fatty acids impinge on CD4+ T cell motility and adipose tissue distribution via direct and lipid mediator-dependent effects
Omega-3 polyunsaturated fatty acids impinge on CD4+ T cell motility and adipose tissue distribution via direct and lipid mediator-dependent effects
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DOI：
10.1093/cvr/cvz208
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发表时间：
2020-04-01
影响因子：
10.8
通讯作者：
Mauro, Claudio
中科院分区：
文献类型：
--
作者：
Cucchi, Danilo;Camacho-Munoz, Dolores;Mauro, Claudio
适应性免疫参与了心血管代谢紊乱（CVMD）的发病机制。ω-3多不饱和脂肪酸（n-3 PUFA）有益于心血管健康，有可能改善与代谢失衡相关的失调适应性免疫反应。我们的目的是探索n-3 PUFA可能改变T细胞运动性和组织分布的机制，以促进CVMD中炎症较少的环境并改善淋巴细胞功能。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-3 PUFA二十碳五烯酸（EPA）和二十二碳六烯酸（DHA），改变活化的CD 4（+）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-3 PUFA的饮食减少了脂肪组织中发现的效应记忆CD 4（+）T细胞的数量，并改变了血浆、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-单酰基甘油、N-酰基乙醇胺和神经酰胺的分布。这些生物活性脂质表现出不同的趋化特性时，在体外与活化的CD 4（+）T细胞的趋化性试验。此外，经EPA和DHA处理的CD 4（+）T细胞显示出化学运动的显著减少，如通过跨内皮迁移测定所评估的，并且当植入受体小鼠时，表现出向发炎腹膜的迁移效率较低。最后，EPA和DHA治疗减少了体外极化的CD 4（+）T细胞的数量，改变了膜微区的磷脂组成，降低了小Rho GTP酶，Rhox，结论EPA和DHA影响CD 4（+）细胞的运动性，通过干扰细胞迁移所需的细胞骨架重排，改变T细胞到达靶组织的能力。这可以至少部分解释n-3 PUFA的抗炎作用，支持其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中的潜在用途。
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 polarized CD4(+) T cells in vitro, altered the phospholipid composition of membrane microdomains and decreased the activity of small Rho GTPases, Rhox, 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.