n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization.
n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization.
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DOI：
10.1016/j.bbamem.2015.10.009
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Chapkin RS
中科院分区：
文献类型：
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作者：
Hou TY;Barhoumi R;Fan YY;Rivera GM;Hannoush RN;McMurray DN;Chapkin RS
鱼油中丰富的n-3多不饱和脂肪酸（n-3 PUFA）发挥抗炎作用的机制尚未严格定义。我们先前已经证明，n-3 PUFA减少了CD 4 + T细胞中磷脂酰肌醇-（4，5）-二磷酸[PI（4，5）P2]的量，导致激活后肌动蛋白重塑受到抑制。由于PI（4，5）P2的离散池存在于质膜中，我们确定n-3 PUFA是否调节PI（4，5）P2相对于筏和非筏结构域的空间组织。我们使用Förster共振能量转移（FRET）来证明富含n-3 PUFA的CD 4 + T细胞质膜中的脂筏中结构域显示增加的Lck（N10）和LAT（ΔCP）的共聚簇，脂筏的标志物。富含n-3 PUFA的CD 4 + T细胞也表现出耗尽的质膜非筏PI（4，5）P2池，如通过Src（N15）（非筏标记物）和PH（PLC-δ）（PI（4，5）P2报告子）的减少的共聚簇所检测的。与外源性PI（4，5）P2孵育挽救了对非筏PI（4，5）P2池的作用，并逆转了对富含n-3 PUFA的CD 4 + T细胞中T细胞增殖的抑制。此外，从喂食富含4%二十二碳六烯酸（DHA）的饮食的小鼠中分离的CD 4 + T细胞表现出PI（4，5）P2的非筏池的减少，并且外源性PI（4，5）P2逆转了T细胞增殖的抑制。最后，这些影响不是由于翻译后脂化的变化，因为n-3 PUFA没有改变信号蛋白的棕榈酰化状态。这些数据表明，n-3 PUFA通过改变质膜形貌和PI（4，5）P2的空间组织来抑制T细胞增殖。
The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4+ T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Förster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4+ T cells enriched in n-3 PUFA display increased co-clustering of Lck(N10) and LAT(ΔCP), markers of lipid rafts. CD4+ T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-δ), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4+ T cells enriched with n-3 PUFA. Furthermore, CD4+ T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2.