ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α
ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α
复制标题
DOI：
10.1096/fj.202001687r
复制
发表时间：
2021-04-01
期刊：
影响因子：
4.8
通讯作者：
Kunisawa, Jun
中科院分区：
文献类型：
--
作者：
Saika, Azusa;Nagatake, Takahiro;Kunisawa, Jun
omega 3 脂肪酸通过转化为脂质介质而显示出强大的生物活性；因此，膳食脂质的代谢是 omega 3 脂肪酸控制过敏性炎症疾病特性的关键决定因素。然而，皮肤中 omega 3 脂肪酸的代谢进程及其在调节皮肤炎症中的作用仍有待阐明。在这项研究中，我们发现 12-羟基二十碳五烯酸 (12-HEPE) 是二十碳五烯酸的 12-脂氧合酶代谢物，是喂食富含 omega-3 脂肪酸的亚麻籽油的小鼠皮肤中积累的主要代谢物。一致的是，Alox12 和 Alox12b（编码参与 12-HEPE 生成的蛋白质）在皮肤中的基因表达水平远高于其他组织（例如肠道）。我们还发现，局部应用 12-HEPE 通过抑制中性粒细胞浸润皮肤来抑制与接触性超敏反应相关的炎症。在体外的人角质形成细胞中，12-HEPE 通过类视黄醇 X 受体 α 抑制编码中性粒细胞趋化剂 CXCL1 和 CXCL2 的两种基因的表达。总之，目前的结果表明，饮食中 omega 3 脂肪酸的代谢进程在不同器官中有所不同，并确定 12-HEPE 是皮肤中主要的 omega 3 脂肪酸代谢物。
omega 3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of omega 3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of omega 3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed omega 3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor alpha. Together, the present results demonstrate that the metabolic progression of dietary omega 3 fatty acids differs in different organs, and identify 12-HEPE as the dominant omega 3 fatty acid metabolite in the skin.