Effects of ω-3 Polyunsaturated Fatty Acids on the Homeostasis of CD4+ T Cells and Lung Injury in Mice With Polymicrobial Sepsis

Abstract 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, 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.

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Lipophilic natural compounds (n‐3 polyunsaturated fatty acids) modulate plasma membrane organization in mouse CD4 + T cells (975.1)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.975.1 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Tim Hou ◽

Rola Barhoumi ◽

Gonzalo Rivera ◽

David McMurray ◽

Robert Chapkin

Keyword(s):

Fatty Acids ◽

T Cells ◽

Plasma Membrane ◽

Polyunsaturated Fatty Acids ◽

Cd4 T Cells ◽

Natural Compounds ◽

Membrane Organization

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Antecedent Administration of Glutamine Benefits the Homeostasis of CD4 + T Cells and Attenuates Lung Injury in Mice With Gut‐Derived Polymicrobial Sepsis

Journal of Parenteral and Enteral Nutrition ◽

10.1002/jpen.1505 ◽

2019 ◽

Vol 43 (7) ◽

pp. 927-936 ◽

Cited By ~ 4

Author(s):

Cing‐Syuan Lei ◽

Jin‐Ming Wu ◽

Po‐Chu Lee ◽

Ting‐Chun Kuo ◽

Po‐Da Chen ◽

...

Keyword(s):

T Cells ◽

Lung Injury ◽

Cd4 T Cells ◽

Polymicrobial Sepsis

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n−3 polyunsaturated fatty acids suppress phosphatidylinositol 4,5-bisphosphate-dependent actin remodelling during CD4+ T-cell activation

Biochemical Journal ◽

10.1042/bj20111589 ◽

2012 ◽

Vol 443 (1) ◽

pp. 27-37 ◽

Cited By ~ 29

Author(s):

Tim Y. Hou ◽

Jennifer M. Monk ◽

Yang-Yi Fan ◽

Rola Barhoumi ◽

Yong Q. Chen ◽

...

Keyword(s):

Fatty Acids ◽

T Cells ◽

T Cell ◽

Polyunsaturated Fatty Acids ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Molecular Mechanisms ◽

Immunological Synapse ◽

Actin Remodelling

n−3 PUFA (polyunsaturated fatty acids), i.e. DHA (docosahexaenoic acid), found in fish oil, exhibit anti-inflammatory properties; however, the molecular mechanisms remain unclear. Since PtdIns(4,5)P2 resides in raft domains and DHA can alter the size of rafts, we hypothesized that PtdIns(4,5)P2 and downstream actin remodelling are perturbed by the incorporation of n−3 PUFA into membranes, resulting in suppressed T-cell activation. CD4+ T-cells isolated from Fat-1 transgenic mice (membranes enriched in n−3 PUFA) exhibited a 50% decrease in PtdIns(4,5)P2. Upon activation by plate-bound anti-CD3/anti-CD28 or PMA/ionomycin, Fat-1 CD4+ T-cells failed to metabolize PtdIns(4,5)P2. Furthermore, actin remodelling failed to initiate in Fat-1 CD4+ T-cells upon stimulation; however, the defect was reversed by incubation with exogenous PtdIns(4,5)P2. When Fat-1 CD4+ T-cells were stimulated with anti-CD3/anti-CD28-coated beads, WASP (Wiskott–Aldrich syndrome protein) failed to translocate to the immunological synapse. The suppressive phenotype, consisting of defects in PtdIns(4,5)P2 metabolism and actin remodelling, were recapitulated in CD4+ T-cells isolated from mice fed on a 4% DHA triacylglycerol-enriched diet. Collectively, these data demonstrate that n−3 PUFA, such as DHA, alter PtdIns(4,5)P2 in CD4+ T-cells, thereby suppressing the recruitment of WASP to the immunological synapse, and impairing actin remodelling in CD4+ T-cells.

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Polyunsaturated Fatty Acids Inhibit T Cell Signal Transduction by Modification of Detergent-insoluble Membrane Domains

The Journal of Cell Biology ◽

10.1083/jcb.143.3.637 ◽

1998 ◽

Vol 143 (3) ◽

pp. 637-644 ◽

Cited By ~ 192

Author(s):

Thomas M. Stulnig ◽

Markus Berger ◽

Thomas Sigmund ◽

Daniel Raederstorff ◽

Hannes Stockinger ◽

...

Keyword(s):

Signal Transduction ◽

Fatty Acids ◽

T Cells ◽

T Cell ◽

Polyunsaturated Fatty Acids ◽

Membrane Domains ◽

Protein Tyrosine ◽

Cell Signal ◽

Family Protein ◽

Cell Signal Transduction

Polyunsaturated fatty acids (PUFAs) exert immunosuppressive effects, but the molecular alterations leading to T cell inhibition are not yet elucidated. Signal transduction seems to involve detergent-resistant membrane domains (DRMs) acting as functional rafts within the plasma membrane bilayer with Src family protein tyrosine kinases being attached to their cytoplasmic leaflet. Since DRMs include predominantly saturated fatty acyl moieties, we investigated whether PUFAs could affect T cell signaling by remodeling of DRMs. Jurkat T cells cultured in PUFA-supplemented medium showed a markedly diminished calcium response when stimulated via the transmembrane CD3 complex or glycosyl phosphatidylinositol (GPI)- anchored CD59. Immunofluorescence studies indicated that CD59 but not Src family protein tyrosine kinase Lck remained in a punctate pattern after PUFA enrichment. Analysis of DRMs revealed a marked displacement of Src family kinases (Lck, Fyn) from DRMs derived from PUFA-enriched T cells compared with controls, and the presence of Lck in DRMs strictly correlated with calcium signaling. In contrast, GPI-anchored proteins (CD59, CD48) and ganglioside GM1, both residing in the outer membrane leaflet, remained in the DRM fraction. In conclusion, PUFA enrichment selectively modifies the cytoplasmic layer of DRMs and this alteration could underlie the inhibition of T cell signal transduction by PUFAs.

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