Transgenic Increase in n-3/n-6 Fatty Acid Ratio Protects Against Cognitive Deficits Induced by an Immune Challenge through Decrease of Neuroinflammation
Transgenic Increase in n-3/n-6 Fatty Acid Ratio Protects Against Cognitive Deficits Induced by an Immune Challenge through Decrease of Neuroinflammation
复制标题
DOI：
10.1038/npp.2014.196
复制
发表时间：
2015-02-01
影响因子：
7.6
通讯作者：
Laye, Sophie
中科院分区：
文献类型：
--
作者：
Delpech, Jean-Christophe;Madore, Charlotte;Laye, Sophie
多不饱和脂肪酸（PUFA）在大脑中显示出免疫调节特性，n-3 PUFA能够减少炎症，而n-6 PUFA更具有促炎性。已经广泛证明，暴露于外周免疫激发导致与认知缺陷相关的脑中炎性介质的产生和释放。问题是，补充n-3 PUFA是否可以下调大脑炎症反应和随后的认知改变。在这项研究中，我们使用了转基因小鼠线携带脂肪-1基因的蛔虫秀丽隐杆线虫，编码n-3多不饱和脂肪酸去饱和酶，催化转化n-6成n-3多不饱和脂肪酸。因此，这些小鼠显示内源性升高的n-3 PUFA组织含量。向Fat-1小鼠或野生型（WT）同窝小鼠外周注射脂多糖（LPS）（一种细菌内毒素），以诱导炎症发作。我们的研究结果表明，LPS不同程度地改变了Fat-1和WT小鼠小胶质细胞的表型以及细胞因子和趋化因子的表达。在Fat-1小鼠中，与WT小鼠相比，促炎因子的合成降低，而抗炎机制在LPS处理后24小时有利。此外，LPS注射损害了WT小鼠的空间记忆，而有趣的是，Fat-1小鼠表现出正常的认知表现。总之，这些数据表明，在Fat-1小鼠中观察到的中枢n-3 PUFA增加调节了脑先天免疫系统活性，从而保护动物免受LPS诱导的促炎细胞因子产生和随后的空间记忆改变。
Polyunsaturated fatty acids (PUFAs) display immunomodulatory properties in the brain, n-3 PUFAs being able to reduce inflammation whereas n-6 PUFAs are more pro-inflammatory. It has been extensively demonstrated that exposure to a peripheral immune challenge leads to the production and release of inflammatory mediators in the brain in association with cognitive deficits. The question arises whether n-3 PUFA supplementation could downregulate the brain inflammatory response and subsequent cognitive alterations. In this study, we used a genetically modified mouse line carrying the fat-1 gene from the roundworm Caenorhabditis elegans, encoding an n-3 PUFA desaturase that catalyzes conversion of n-6 into n-3 PUFA. Consequently, these mice display endogenously elevated n-3 PUFA tissue contents. Fat-1 mice or wild-type (WT) littermates were injected peripherally with lipopolysaccharide (LPS), a bacterial endotoxin, to induce an inflammatory episode. Our results showed that LPS altered differently the phenotype of microglia and the expression of cytokines and chemokines in Fat-1 and WT mice. In Fat-1 mice, pro-inflammatory factors synthesis was lowered compared with WT mice, whereas anti-inflammatory mechanisms were favored 24 h after LPS treatment. Moreover, LPS injection impaired spatial memory in WT mice, whereas interestingly, the Fat-1 mice showed normal cognitive performances. All together, these data suggest that the central n-3 PUFA increase observed in Fat-1 mice modulated the brain innate immune system activity, leading to the protection of animals against LPS-induced pro-inflammatory cytokine production and subsequent spatial memory alteration.