ω3脂肪酸代谢物12-羟基二十碳五烯酸通过类视色素X受体α下调角质形成细胞中CXCL1和CXCL2基因的表达，从而减轻接触超敏性,The FASEB Journal

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ω3脂肪酸代谢物12-羟基二十碳五烯酸通过类视色素X受体α下调角质形成细胞中CXCL1和CXCL2基因的表达，从而减轻接触超敏性
The FASEB Journal ( IF 4.4 ) Pub Date : 2021-03-22 , DOI: 10.1096/fj.202001687r
Azusa Saika _{1,

2} , Takahiro Nagatake ₁ , So-Ichiro Hirata ₁ , Kento Sawane _{1,

2,

3} , Jun Adachi ₄ , Yuichi Abe _{4,

5} , Junko Isoyama ₄ , Sakiko Morimoto ₁ , Eri Node ₁ , Prabha Tiwari ₁ , Koji Hosomi ₁ , Ayu Matsunaga _{1,

6} , Tetsuya Honda _{7,

8} , Takeshi Tomonaga ₄ , Makoto Arita _{9,

10,

11} , Kenji Kabashima ₇ , Jun Kunisawa _{1,

2,

12,

13,

14}

Affiliation

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
Nippon Flour Mills Co., Ltd, Innovation Center, Atsugi, Japan.
Laboratory of Proteome Research and Laboratory of Proteomics for Drug Discovery, NIBIOHN, Osaka, Japan.
Division of Molecular Diagnosis, Aichi Cancer Center Research Institute, Nagoya, Japan.
Department of Food and Life Science, School of Life and Environmental Science, Azabu University, Sagamihara, Japan.
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Dermatology, Hamamatsu University School of Medicine, Shizuoka, Japan.
Division of Physiological Chemistry and Metabolism, Faculty of Pharmacy, Keio University, Tokyo, Japan.
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.
International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Graduate School of Medicine, Graduate School of Dentistry, Osaka University, Suita, Japan.

ω3脂肪酸通过转化为脂质介体显示出强大的生物活性。因此，饮食脂质的代谢是控制过敏性炎症性疾病中ω3脂肪酸特性的关键决定因素。然而，ω3脂肪酸在皮肤中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-脂氧合酶代谢产物，是富含ω3脂肪酸的亚麻籽油喂养小鼠皮肤中积累的主要代谢产物。一致地，Alox12和Alox12b的基因表达水平，其编码参与12-HEPE生成的蛋白质，在皮肤中的含量远高于其他组织（例如肠）。我们还发现，局部应用12-HEPE可通过抑制嗜中性粒细胞浸润皮肤来抑制与接触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抑制两个编码中性粒细胞趋化因子CXCL1和CXCL2的基因的表达。总之，本研究结果表明，饮食中ω3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ω3脂肪酸代谢产物。

"点击查看英文标题和摘要"

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 acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 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 ω3 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 α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12‐HEPE as the dominant ω3 fatty acid metabolite in the skin.

更新日期：2021-03-22

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