The 17,18-epoxyeicosatetraenoic acid–G protein–coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques - 04/08/18
Doi : 10.1016/j.jaci.2017.09.053
Takahiro Nagatake, PhD a, Yumiko Shiogama, DVM b, Asuka Inoue, PhD c, Junichi Kikuta, MD, PhD d, Tetsuya Honda, MD, PhD e, Prabha Tiwari, PhD a, Takayuki Kishi, BSc c, Atsushi Yanagisawa d, Yosuke Isobe, PhD f, Naomi Matsumoto, BSc a, Michiko Shimojou, MSc a, Sakiko Morimoto, MSc a, Hidehiko Suzuki, PhD a, So-ichiro Hirata, MSc a, g, Pär Steneberg, PhD h, Helena Edlund, PhD h, Junken Aoki, PhD c, Makoto Arita, PhD f, i, j, Hiroshi Kiyono, DDS, PhD k, l, Yasuhiro Yasutomi, DVM, PhD b, m, Masaru Ishii, MD, PhD d, Kenji Kabashima, MD, PhD e, Jun Kunisawa, PhD a, g, k, n, ⁎ 
a 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), Ibaraki, Japan
b Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, NIBIOHN, Tsukuba, Japan
c Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
d Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Japan
n Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, Graduate School of Dentistry, Osaka University, Suita, Japan
e Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
f Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
g Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan
h Umea Center for Molecular Medicine, Umea University, Umea, Sweden
i Graduate School of Medical Life Science, Yokohama City University, Tsurumi-ku, Yokohama, Japan
j Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan
k Division of Mucosal Immunology, Department of Microbiology and Immunology and International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan
l Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
m Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Japan
∗Corresponding author: Jun Kunisawa, PhD, Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, NIBIOHN, 7-6-8 Asagi Saito, Ibaraki, Osaka 567-0085, Japan.Laboratory of Vaccine MaterialsCenter for Vaccine and Adjuvant Research and Laboratory of Gut Environmental SystemNIBIOHN7-6-8 Asagi Saito, IbarakiOsaka567-0085Japan
Abstract |
Background |
Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.
Objective |
We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.
Methods |
Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.
Results |
We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein–coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.
Conclusion |
17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : 17,18-Epoxyeicosatetraenoic acid, G protein–coupled receptor 40, ω3 fatty acid, contact hypersensitivity, dermatitis, neutrophil
Abbreviations used : ALA, APC, Chi3l3, CYP, DAPI, DC, DNFB, DHA, 17,18-diHETE, EPA, 17,18-EpETE, FasL, FITC, fMLP, GPR, G-CSF, HEK293, ICAM, iSALT, NIBIOHN, PE, PPAR
Plan
| Supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) and the Japan Society for the Promotion of Science (JSPS; KAKENHI [JP15K19142 to T.N., JP17K08264 to A.I., JP15K09766 to T.H., JP17K08301 to H.S., JP15H05897 to J.A., JP15H04648 to M.A., JP15K15417 and JP15H02551 to K.K., JP15H05790 to K.K. and J.K., and JP26670241 and JP26293111 to J.K.]); the Japan Science and Technology Agency (JST), PRESTO (to A.I.; JPMJPR1331); the Japan Agency for Medical Research and Development (AMED; [JP17ek0410032h0002 to H.K., JP17gm5910013 to A.I., JP17gm0710001 to J.A. and JP17ek0410032s0102, JP17ek0210078h0002, JP17ak0101068h0001 and JP17gm1010006s0101 to J.K.]); the Ministry of Health and Welfare of Japan (to J.K.); the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry (to M.A. and J.K.); a grant-in-aid for Scientific Research on Innovative Areas from MEXT (JP15H05906 to T.H.; JP3701, JP15K21738, JP15H05898, and JP15H05897 to M.A.; JP15H01155 to K.K.; JP23116506 to H.K. and J.K.; and JP16H01373 and JP25116706 to J.K.); the Strategic Research Program in Diabetes at Umea University (to H.E. and P.S.); the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo (to J.K.); the Astellas Foundation for Research on Metabolic Disorders (to J.K.); Terumo Foundation for Life Sciences and Arts (to J.K.); the Nipponham Foundation for the Future of Food; and the Suzuken Memorial Foundation (to J.K.); the Canon Foundation (to J.K.). Y.I. was supported by a RIKEN Special Postdoctoral Researcher Program. P.T. was supported by a fellowship from the Tokyo Biochemical Research Foundation and Takeda Science Foundation. T.K. was supported by a JSPS Research Fellowship. |
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| Disclosure of potential conflict of interest: T. Nagatake, T. Kishi, and H. Suzuki have received grants from the Japan Society for the Promotion of Science. A. Inoue has received grants from the Japan Science and Technology Agency, the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, and Ono Medical Research Foundation and has a patent for a method for detecting signal transduction of G protein–coupled receptor (WO2015128894A1). T. Honda has received grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Japan Society for the Promotion of Science; Mitsubishi Tanabe Pharma; Sanofi Japan Group; AbbVie GK; the Lydia O'Leary Memorial Dermatological Foundation; ROHTO Pharmaceutical; Shiseido; Novartis International AG; and Kao Co and has received payment for lectures from Novartis International AG, AbbVie GK, Sanofi Japan Group, Mitsubishi Tanabe Pharma, Janssen Pharma, Kyowa Hakko Kirin, and Torii Pharmaceutical. P. Tiwari has received grants from the Tokyo Biochemical Research Foundation and Takeda Science Foundation. H. Edlund has a board membership with and receives stock/stock options from Betagenon AB. J. Aoki has received grants from the Japan Agency for Medical Research and Development; the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ono Pharmaceutical; Kyorin Pharmaceutical; Astellas Pharma; the Japan Society for the Promotion of Science; and Tosoh and has a patent for a method for detecting signal transduction of G protein–coupled receptor (WO2015128894A1). M. Arita has received grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry; and the Japan Society for the Promotion of Science. H. Kiyono has received grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Japan Agency for Medical Research and Development and is employed by the University of Tokyo, Chiba University, and the Japan Society for the Promotion of Science. K. Kabashima has received grants from the Japan Society for the Promotion of Science, Sanofi Japan Group, Mitsubishi Tanabe Pharma, Chugai Pharmaceutical, Pola Pharma, Maruho, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan; has received payment for lectures from Pola Pharma, Kyowa Hakko Kirin, Maruho, and Leo Pharma; and has received payment for writing the manuscript from Sanofi Japan Group. J. Kunisawa has received grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Japan Agency for Medical Research and Development; the Ministry of Health and Welfare of Japan; the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry; the Japan Society for the Promotion of Science; the Astellas Foundation for Research on Metabolic Disorders; the Terumo Foundation for Life Sciences and Arts; the Nipponham Foundation for the Future of Food; Suzuken Memorial Foundation; Ono Pharmaceutical; MGP; Nitto Pharma; Morinaga Milk; and Nippon Flour Mills; has consultant arrangements with EA Pharma, Suntory Holdings, and Ono Pharmaceutical. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2017
The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 142 - N° 2
P. 470 - août 2018 Retour au numéro
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