Omega-3 polyunsaturated fatty acids reverse the impact of western diets on regulatory T cell responses through averting ceramide-mediated pathways

Dolores Camacho-Muñoz, Jennifer Niven, Salih Kucuk, Danilo Cucchi, Michelangelo Certo, Simon W Jones, Deborah P Fischer, Claudio Mauro, Anna Nicolaou*

*Corresponding author for this work

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Abstract

Western diet (WD), high in sugar and fat, promotes obesity and associated chronic low-grade pro-inflammatory environment, leading to impaired immune function, reprogramming of innate and adaptive immune cells, and development of chronic degenerative diseases, including cardiovascular disease. Increased concentrations of circulating and tissue ceramides contribute to inflammation and cellular dysfunction common in immune metabolic and cardiometabolic disease. Therefore, ceramide-lowering interventions have been considered as strategies to improve adipose tissue health.

Here, we report the ability of omega-3 polyunsaturated fatty acids (n-3PUFA) to attenuate inflammatory phenotypes promoted by WD, through ceramide-dependent pathways. Using an animal model, we show that enrichment of WD diet with n-3PUFA, reduced the expression of ceramide synthase 2 (CerS2), and lowered the concentration of long-chain ceramides (C23-C26) in plasma and adipose tissues. N-3PUFA also increased prevalence of the anti-inflammatory CD4+Foxp3+ and CD4+Foxp3+CD25+ Treg subtypes in lymphoid organs. The CerS inhibitor FTY720 mirrored the effect of n-3PUFA. Treatment of animal and human T cells with ceramide C24 in vitro, reduced CD4+Foxp3+ Treg polarisation and IL-10 production, and increased IL-17, while it decreased Erk and Akt phosphorylation downstream of T cell antigen receptors (TCR). These findings suggest that molecular mechanisms mediating the adverse effect of ceramides on regulatory T lymphocytes, progress through reduced TCR signalling.

Our findings suggest that nutritional enrichment of WD with fish oil n-3PUFA can partially mitigate its detrimental effects, potentially improving the low-grade inflammation associated with immune metabolic disease. Compared to pharmacological interventions, n-3PUFA offer a simpler approach that can be accommodated as lifestyle choice.

Original languageEnglish
Article number115211
Number of pages12
JournalBiochemical Pharmacology
Volume204
Early online date17 Aug 2022
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Funding Information:
The work has been supported by a grant from the British Heart Foundation (PG/15/105/31906) to A.N. and C.M. C.M. is supported by a British Heart Foundation Intermediate Basic Science Research Fellowship (FS/12/38/29640) and a Professorial Fellowship from the University of Birmingham. The authors wish to thank Neil O’Hara (University of Manchester) for excellent technical support and Dr Jorge Caamano (University of Birmingham) for support in experimental design and intellectual contribution.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Adipose tissue
  • Ceramide synthase
  • Ceramides
  • High fat western diet
  • Omega 3 polyunsaturated fatty acids
  • Regulatory T cells

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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