Papers - Arita, Makoto

A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling.

Yamada M, Takahashi N, Matsuda Y, Sato K, Yokoji M, Sulijaya B, Maekawa T, Ushiki T, Mikami Y, Hayatsu M, Mizutani Y, Kishino S, Ogawa J, Arita M, Tabeta K, Maeda T, *Yamazaki K.

Sci Rep (Scientific Reports)  8 ( 1 ) 9008 2018

Research paper (scientific journal), Joint Work, Accepted

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© 2018 The Author(s). Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells; activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.

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Facile determination of sphingolipids under alkali condition using metal-free column by LC-MS/MS.

Gowda SG, Ikeda K, *Arita M.

Anal Bioanal Chem (Analytical and Bioanalytical Chemistry)  410 ( 20 ) 4793 - 4803 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  16182642

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© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Extraction and analysis of sphingolipids from biological samples is a critical step in lipidomics, especially for minor species such as sphingoid bases and sphingosine-1-phosphate. Although several liquid chromatography-mass spectrometry methods enabling the determination of sphingolipid molecular species have been reported, they were limited in analytical sensitivity and reproducibility by causing significant peak tailing, especially by the presence of phosphate groups, and most of the extraction techniques are laborious and do not cover a broad range of sphingolipid metabolites. In this study, we developed a rapid single-phase extraction and highly sensitive analytical method for the detection and quantification of sphingolipids (including phosphates) comprehensively using liquid chromatography-triple quadruple mass spectrometry. After validating the reliability of the method, we analyzed the intestinal tissue sphingolipids of germ-free (GF) and specific pathogen-free (SPF) mice and found significantly higher levels of free sphingoid bases and sphingosine-1-phosphate in the GF condition as compared to the SPF condition. This method enables a rapid extraction and highly sensitive determination of sphingolipids comprehensively at low femtomolar ranges. [Figure not available: see fulltext.].

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17,18-EpETE-GPR40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques.

Nagatake T, Shiogama Y, Inoue A, Kikuta J, Honda T, Tiwari P, Kishi T, Yanagisawa A, Isobe Y, Matsumoto N, Shimojou M, Morimoto S, Suzuki H, Hirata S, Steneberg P, Edlund H, Aoki J, Arita M, Kiyono H, Yasutomi Y, Ishii M, Kabashima K, *Kunisawa J.

J Allergy Clin Immunol (Journal of Allergy and Clinical Immunology)  142 ( 2 ) 470 - 484 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00916749

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© 2017 The Authors 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.

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Thromboxane A2 facilitates IL-17A production from Vγ4+ γδT cells and promotes psoriatic dermatitis in mice.

1. Ueharaguchi Y, *Honda T, Kusuba N, Hanakawa S, Adachi A, Sawada Y, Otsuka A, Kitoh A, Dainichi T, Egawa G, Nakashima C, Nakajima S, Murata T, Ono S, Arita M, Narumiya S, Miyachi Y, Kabashima K.

J Allergy Clin Immunol (Journal of Allergy and Clinical Immunology)  142 ( 2 ) 680 - 683 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00916749

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MS-based lipidomics of human blood plasma – a community-initiated position paper to develop accepted guidelines.

Burla B, Arita M, Arita M, Bendt AK, Cazenave-Gassiot A, Dennis EA, Ekroos K, Han X, Ikeda K, Liebisch G, Lin MK, Loh TP, Meikle PJ, Oresic M, Quehenberger O, Shevchenko A, Torta F, Wakelam MJO, Wheelock CE, *Wenk MR

J Lipid Res (Journal of Lipid Research)  59 ( 10 ) 2001 - 2017 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00222275

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Copyright © 2018 Burla et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. Human blood is a self-regenerating lipid-rich biological fluid that is routinely collected in hospital settings. The inventory of lipid molecules found in blood plasma (plasma lipidome) offers insights into individual metabolism and physiology in health and disease. Disturbances in the plasma lipidome also occur in conditions that are not directly linked to lipid metabolism; therefore, plasma lipidomics based on MS is an emerging tool in an array of clinical diagnostics and disease management. However, challenges exist in the translation of such lipidomic data to clinical applications. These relate to the reproducibility, accuracy, and precision of lipid quantitation, study design, sample handling, and data sharing. This position paper emerged from a workshop that initiated a community-led process to elaborate and define a set of generally accepted guidelines for quantitative MS-based lipidomics of blood plasma or serum, with harmonization of data acquired on different instrumentation platforms across independent laboratories as an ultimate goal. We hope that other fields may benefit from and follow such a precedent.

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Reelin deficiency leads to aberrant lipid composition in mouse brain.

Mizukami T, Ikeda K, Shimanaka Y, Korogi K, Zhou C, Takase H, Tsuiji H, Kono N, Kohno T, Arai H, Arita M, *Hattori M.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications)  505 ( 1 ) 81 - 86 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

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© 2018 Elsevier Inc. Reelin is a secreted protein essential for the development and function of the mammalian brain. The receptors for Reelin, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, belong to the low-density lipoprotein receptor family, but it is not known whether Reelin is involved in the brain lipid metabolism. In the present study, we performed lipidomic analysis of the cerebral cortex of wild-type and Reelin-deficient (reeler) mice, and found that reeler mice exhibited several compositional changes in phospholipids. First, the ratio of phospholipids containing one saturated fatty acid (FA) and one docosahexaenoic acid (DHA) or arachidonic acid (ARA) decreased. Secondly, the ratio of phospholipids containing one monounsaturated FA (MUFA) and one DHA or ARA increased. Thirdly, the ratio of phospholipids containing 5,8,11-eicosatrienoic acid, or Mead acid (MA), increased. Finally, the expression of stearoyl-CoA desaturase-1 (SCD-1) increased. As the increase of MA is seen as an index of polyunsaturated FA (PUFA) deficiency, and the expression of SCD-1 is suppressed by PUFA, these results strongly suggest that the loss of Reelin leads to PUFA deficiency. Hence, MUFA and MA are synthesized in response to this deficiency, in part by inducing SCD-1 expression. This is the first report of changes of FA composition in the reeler mouse brain and provides a basis for further investigating the new role of Reelin in the development and function of the brain.

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An omega-3 polyunsaturated fatty acid derivative, 18-HEPE, protects against CXCR4-associated melanoma metastasis.

Li J, Chen CY, Arita M, Kim K, Li X, Zhang H, *Kang JX.

Carcinogenesis (Carcinogenesis)  39 ( 11 ) 1380 - 1388 2018

Research paper (scientific journal), Joint Work, Accepted

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Melanoma has a high propensity to metastasize and exhibits a poor response to classical therapies. Dysregulation of the chemokine receptor gene CXCR4 is associated with melanoma progression, and although n-3 polyunsaturated fatty acids (PUFAs) are known to be beneficial for melanoma prevention, the underlying mechanism of this effect is unclear. Here, we used the n-3 fatty acid desaturase (Fat-1) transgenic mouse model of endogenous n-3 PUFA synthesis to investigate the influence of elevated n-3 PUFA levels in a mouse model of metastatic melanoma. We found that relative to wild-type (WT) mice, Fat-1 mice exhibited fewer pulmonary metastatic colonies and improved inflammatory indices, including reduced serum tumor necrosis factor alpha (TNF-α) levels and pulmonary myeloperoxidase activity. Differential PUFA metabolites in serum were considered a key factor to alter cancer cell travelling to lung, and we found that n-6 PUFAs such as arachidonic acid induced CXCR4 protein expression although n-3 PUFAs such as eicosapentaenoic acid (EPA) decreased CXCR4 levels. In addition, serum levels of the bioactive EPA metabolite, 18-HEPE, were elevated in Fat-1 mice relative to WT mice, and 18-HEPE suppressed CXCR4 expression in B16-F0 cells. Moreover, relative to controls, numbers of pulmonary metastatic colonies were reduced in WT mice receiving intravenous injections either of 18-HEPE or 18-HEPE-pretreated melanoma cells. Our results indicate that 18-HEPE is a potential anticancer metabolite that mediates, at least in part, the preventive effect of n-3 PUFA on melanoma metastasis.

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PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Hirabayashi T, Anjo T, Kaneko A, Senoo Y, Shibata A, Takama H, Yokoyama K, Nishito Y, Ono T, Taya C, Muramatsu K, Fukami K, Muñoz-Garcia A, Brash AR, Ikeda K, Arita M, Akiyama M, *Murakami M.

Nature Commun 8   14609 2017

Research paper (scientific journal), Joint Work, Accepted

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Comprehensive identification of sphingolipid species by in silico retention time and tandem mass spectral library.

Tsugawa H, Ikeda K, Tanaka W, Senoo Y, *Arita M, *Arita M

J Cheminform 9   19 2017

Research paper (scientific journal), Joint Work, Accepted

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Prolonged activation of IL-5 producing ILC2 causes pulmonary arterial hypertrophy.

Ikutani M, Tsuneyama K, Kawaguchi K, Fukuoka J, Kudo F, Nakae S, Arita M, Nagai Y, Takaki S, *Takatsu K.

JCI Insight 2   e90721 2017

Research paper (scientific journal), Joint Work, Accepted

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Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity.

Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima-Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo M, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, *Ohtani N.

Cancer Discov 7   522 - 538 2017

Research paper (scientific journal), Joint Work, Accepted

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Autotaxin-lysophosphatidic acid-LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways.

Aikawa S, Kano K, Inoue A, Wang J, Saigusa D, Nagamatsu T, Hirota Y, Fujii T, Tsuchiya S, Taketomi Y, Sugimoto Y, Murakami M, Arita M, Kurano M, Ikeda H, Yatomi Y, Chun J, *Aoki J.

EMBO J 36   2146 - 2160 2017

Research paper (scientific journal), Joint Work, Accepted

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Therapeutic effects of flurbiprofen axetil on mesenteric traction syndrome: randomized clinical trial.

Takahashi H, Shida D, Tagawa K, Iwamoto R, Arita M, Arai H, Suzuki T.

BMC Surg 17   90 2017

Research paper (scientific journal), Joint Work, Accepted

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Comprehensive analyses of oxidized phospholipids using a measured MS/MS spectra library.

Aoyagi R, Ikeda K, Isobe Y, *Arita M

J Lipid Res 58   2229 - 2237 2017

Research paper (scientific journal), Joint Work, Accepted

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ω3 fatty acid epoxides are autocrine mediators that ensure full activation of mast cells.

Shimanaka Y, Kono N, Taketomi Y, Arita M, Okayama Y, Tanaka Y, Nishito Y, Mochizuki T, Kusuhara H, Adibekian A, Cravatt BF, *Murakami M, *Arai H.

Nat Med 23   1287 - 1297 2017

Research paper (scientific journal), Joint Work, Accepted

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Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation.

Yotsumoto S, Muroi Y, Chiba T, Ohmura R, Yoneyama M, Magarisawa M, Dodo K, Terayama N, Sodeoka M, Aoyagi R, Arita M, Arakawa S, Shimizu S, *Tanaka M.

Sci Rep 7   16026 2017

Research paper (scientific journal), Joint Work, Accepted

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Maternal dietary balance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites.

Sakayori N, Kikkawa T, Tokuda H, Kiryu E, Yoshizaki K, Kawashima H, Yamada T, Arai H, Kang JX, Katagiri H, Shibata H, Innis SM, Arita M, *Osumi N.

Stem Cells 34   470 - 482 2016

Research paper (scientific journal), Joint Work, Accepted

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Heterogenous fibroblasts underlie age-dependent tertially lymphoid tissues in the kidney.

Sato Y, Mii A, Hamazaki Y, Fujita H, Nakata H, Masuda K, Nishiyama S, Shibuya S, Haga H, Ogawa O, Shimizu A, Narumiya S, Kaisho T, Arita M, Yanagisawa M, Miyasaka M, Sharma K, Minato N, Kawamoto H, *Yanagita M.

JCI Insight １   e87680 2016

Research paper (scientific journal), Joint Work, Accepted

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Chronic arachidonic acid administration decreases docosahexaenoic acid and eicosapentaenoic acid-derived metabolites in kidneys of aged rats.

Katakura M, *Hashimoto M, Inoue T, Mamun AA, Tanabe Y, Arita M, Shido O.

PLoS One 10   e0140884 2015

Research paper (scientific journal), Joint Work, Accepted

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Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses.

Sawada Y, *Honda T, Hanakawa S, Nakamizo S, Murata T, Ueharaguchi-Tanada Y, Ono S, Amano W, Nakajima S, Egawa G, Tanizaki H, Otsuka A, Kitoh A, Dainichi T, Ogawa N, Kobayashi Y, Yokomizo T, Arita M, Nakamura M, Miyachi Y, *Kabashima K.

J Exp Med 212   1921 - 1930 2015

Research paper (scientific journal), Joint Work, Accepted

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