Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization
Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization
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DOI：
10.1111/j.1471-4159.2007.05129.x
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发表时间：
2008-04-01
影响因子：
4.7
通讯作者：
Laye, Sophie
中科院分区：
文献类型：
--
作者：
De Smedt-Peyrusse, Veronique;Sargueil, Francoise;Laye, Sophie
小胶质细胞对革兰氏阴性细菌内毒素脂多糖（LPS）的识别是通过其与特异性受体（分化簇14和toll样受体-4）的结合而发生的。LPS与这些受体的结合触发促炎细胞因子的合成，所述促炎细胞因子协调脑先天免疫应答以保护CNS免受感染。二十二碳六烯酸（DHA）是一种n-3多不饱和脂肪酸，在大脑中高度整合，是一种有效的免疫调节剂。在这项研究中，我们研究了DHA是否调节LPS受体定位，并因此，LPS诱导的信号通路和促炎细胞因子的产生。我们证明，DHA，当加入外源性，是特别丰富的膜磷脂，但不是在筏脂的小胶质细胞。DHA掺入膜损伤LPS受体分化簇14和Toll样受体-4的表面呈递，但不是它们的膜亚结构域定位。DHA抑制LPS诱导的核因子κ B活化，因此，LPS诱导的促炎细胞因子白细胞介素-1 β和肿瘤坏死因子α的合成被强烈减弱。我们认为DHA通过靶向LPS受体表面位置，从而减少LPS对小胶质细胞的作用，具有高度抗炎作用。这种效应代表了一种新的见解，即DHA在大脑中调节促炎细胞因子的表达以响应细菌产物。
Recognition of lipopolysaccharide (LPS), the endotoxin of gram-negative bacteria, by microglia occurs through its binding to specific receptors, cluster of differentiation 14 and toll-like receptor-4. LPS binding to these receptors triggers the synthesis of proinflammatory cytokines that coordinate the brain innate immune response to protect the CNS of the infection. Docosahexaenoic acid (DHA), a n-3 polyunsaturated fatty acid highly incorporated in the brain, is a potent immunomodulator. In this study, we investigated whether DHA modulates LPS receptor localization and, as a consequence, LPS-induced signaling pathway and proinflammatory cytokine production. We demonstrated that DHA, when added exogenously, is specifically enriched in membrane phospholipids, but not in raft lipids of microglial cells. DHA incorporation in membrane impaired surface presentation of LPS receptors cluster of differentiation 14 and toll-like receptor-4, but not their membrane subdomain localization. LPS-induced nuclear factor kappa B activation was inhibited by DHA, hence, LPS-induced proinflammatory cytokine synthesis of interleukin-1 beta and tumor necrosis factor alpha was strongly attenuated. We suggest that DHA is highly anti-inflammatory by targeting LPS receptor surface location, therefore reducing LPS action on microglia. This effect represents a new insight by which DHA modulates in the brain the expression of proinflammatory cytokines in response to bacterial product.