Genetic deletion of Cyp4f18 disrupts the omega-3 epoxidation pathway and results in psoriasis-like dermatitis

Mio Yoshida, Tomoaki Ishihara, Yosuke Isobe, Makoto Arita

Research output: Contribution to journalArticlepeer-review

Abstract

Cyp4f18 catalyzes the conversion of n-3 polyunsaturated fatty acids (PUFAs) into omega-3 epoxides, such as 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) and 19,20-epoxydocosapentaenoic acid (19,20-EpDPE) from eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), respectively. Cyp4f18-deficient mice spontaneously develop psoriasis-like dermatitis. A significant increase in the number of IL-17A-positive gamma delta (γδ) T cells in the skin and enlargement of draining lymph nodes was observed. These symptoms were drastically suppressed by antibiotic treatment. Cyp4f18 is highly expressed in dendritic cells (DCs), and Cyp4f18-deficient bone marrow-derived dendritic cells (BMDCs) show markedly increased expression levels of cytokines such as IL-23 and IL-1β in response to lipopolysaccharide (LPS) stimulation. Lipidomic analysis of lymph nodes and BMDCs revealed a significant decrease in a series of omega-3 epoxidized metabolites. Among them, 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), a vicinal diol derived from EPA omega-3 epoxidation suppressed IL-23 production in LPS-stimulated BMDCs in Cyp4f18-deficient mice. These results demonstrate that Cyp4f18 endogenously produces omega-3-epoxidized metabolites in the draining lymph nodes, and these metabolites contribute to skin homeostasis by suppressing the excessive activation of the IL-23/IL-17 axis initiated by DCs.

Original languageEnglish
Article numbere22648
JournalFASEB Journal
Volume36
Issue number12
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • dendritic cell
  • fatty acid metabolism
  • lipid mediator
  • n-3 polyunsaturated fatty acids
  • psoriasis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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