Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance
Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance
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Toll 样受体 2/4、单酰基甘油脂肪酶和环氧合酶在社交失败压力诱导的大脑前列腺素 E2 合成中的作用及其行为相关性
DOI：
10.1038/s41598-019-54082-5
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发表时间：
2019
影响因子：
4.6
通讯作者：
Furuyashiki Tomoyuki
中科院分区：
文献类型：
--
作者：
Nie Xiang;Kitaoka Shiho;Shinohara Masakazu;Kakizuka Akira;Narumiya Shuh;Furuyashiki Tomoyuki
大脑和外周的炎症与精神疾病的压力相关病理学有关。我们已经表明，前列腺素（PG）E2，花生四烯酸衍生的脂质介质，和先天免疫受体Toll样受体（TLR）2/4是至关重要的反复应激诱导的行为变化的啮齿动物。然而，应激如何诱导脑内PGE 2的合成以及TLR 2/4是否参与PGE 2的合成尚不清楚。使用缺乏TLR 2和TLR 4的小鼠组合，在这里，我们表明，社会失败应激（SDS）诱导PGE 2的合成在皮层下，但不是皮质，组织中的TLR 2/4依赖的方式。已知脑中的PGE 2主要通过单酰基甘油脂肪酶（MAGL）介导的内源性大麻素2-花生四烯酸酰甘油转化为游离花生四烯酸（用于PGE 2合成的环氧合酶（考克斯）的底物）来获得。我们发现，TLR 2/4缺失降低了重复SDS后皮质下组织中MAGL和COX 1的mRNA表达。MAGL和COX 1以及COX 2的扰动取消SDS诱导的皮质下组织中PGE 2的合成。此外，全身给药JZL 184，MAGL抑制剂，消除重复SDS诱导的社会回避。这些结果表明，SDS诱导PGE 2合成在大脑皮层下区域通过MAGL-COX途径在TLR 2/4依赖的方式，从而导致社会回避。
Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E2, an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE2synthesis in the brain and whether TLR2/4 are involved in the PGE2synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE2synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE2in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE2synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE2synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE2synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.