神经酰胺
FOXP3型
免疫系统
炎症
生物
脂肪组织
调节性T细胞
神经酰胺合酶
T细胞
多不饱和脂肪酸
白细胞介素2受体
免疫学
内分泌学
脂质信号
内科学
医学
细胞凋亡
生物化学
脂肪酸
作者
Dolores Camacho‐Muñoz,Jennifer Niven,Salih Kucuk,Danilo Cucchi,Michelangelo Certo,Simon W. Jones,Deborah Fischer,Claudio Mauro,Anna Nicolaou
标识
DOI:10.1016/j.bcp.2022.115211
摘要
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.
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