Abstract
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.
Highlights
As we have recently shown, fat overload leads to a biased differentiation of a proinflammatory effector memory-like population of CD4þ T cells, both in humans and mice, contributing to the low-grade inflammation observed in obesity.[5]
In the n-3PUFA supplemented animals (CD þ x3 group), the overall number of CD4þ T cells, was not significantly different as compared to untreated controls (CD group); no difference was observed in the number of CD4þ T cells found in the lymphoid organs (Figures 1A and Supplementary material online, Figure S1A)
Analysis of the regulatory CD25þFoxp3þ (Treg) CD4þ T cells, showed a trend towards an increase in the Treg population found in the fat tissues of animals fed the n-3PUFA-supplemented diet, as compared to animals fed standard chow diet (CD) (Figure 1F and Supplementary material online, Figure S1E)
Summary
The omega-3 (n-3) polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, found in fish oils, have been explored as means of preventing cardiovascular disease and improving cardiometabolic risk factors.[6,7,8] the efficiency of n-3PUFA is debated, recent clinical studies have shown that EPA supplementation can reduce the risk of ischemic events and increase the stability of the atherosclerotic plaque, with EPA plaque levels inversely related to their T cell content.[9,10,11,12] n-3PUFA suppress antigen presentation, activation, and proliferation, and lower the expression of cytokines by T cells.[13,14,15] While the immunomodulatory properties of n-3PUFA are appreciated, the underpinning molecular mechanisms are not fully understood. Recent findings indicate that EPA induces the differentiation of regulatory T cells through the up-regulation of peroxisome proliferator-activated receptor c,16 while DHA alters the composition and molecular organization of membrane microdomains, with consequent changes in the activity of signalling proteins linked to actin remodelling, overall, leading to reduced CD4þ T cell activation.[17,18,19]
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