TY - JOUR
T1 - Genetic deletion of Cyp4f18 disrupts the omega-3 epoxidation pathway and results in psoriasis-like dermatitis
AU - Yoshida, Mio
AU - Ishihara, Tomoaki
AU - Isobe, Yosuke
AU - Arita, Makoto
N1 - Funding Information:
This work was supported by the JSPS KAKENHI 15H05897, 15H05898, 20H00495 (M.A.), RIKEN Pioneering Project “Glyco-Lipidologue Initiative” (M.A.), JST-ERATO “ARITA Lipidome Atlas Project” grant number JPMJER2101 (M.A.), RIKEN Junior Research Associate Program, and the Keio University Doctorate Student Grant-in-Aid Program from the Ushioda Memorial Fund (M.Y.).
Funding Information:
This work was supported by the JSPS KAKENHI 15H05897, 15H05898, 20H00495 (M.A.), RIKEN Pioneering Project “Glyco‐Lipidologue Initiative” (M.A.), JST‐ERATO “ARITA Lipidome Atlas Project” grant number JPMJER2101 (M.A.), RIKEN Junior Research Associate Program, and the Keio University Doctorate Student Grant‐in‐Aid Program from the Ushioda Memorial Fund (M.Y.).
Publisher Copyright:
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - dendritic cell
KW - fatty acid metabolism
KW - lipid mediator
KW - n-3 polyunsaturated fatty acids
KW - psoriasis
UR - http://www.scopus.com/inward/record.url?scp=85141938159&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141938159&partnerID=8YFLogxK
U2 - 10.1096/fj.202200982R
DO - 10.1096/fj.202200982R
M3 - Article
C2 - 36374250
AN - SCOPUS:85141938159
SN - 0892-6638
VL - 36
JO - FASEB Journal
JF - FASEB Journal
IS - 12
M1 - e22648
ER -