Papers - Arita, Makoto

Characterization of lipid profiles after dietary intake of polyunsaturated fatty acids using integrated untargeted and targeted lipidomics.

Naoe S, Tsugawa H, Takahashi M, Ikeda K, Arita M.

Metabolites 9   241 2019.10

Research paper (scientific journal), Joint Work, Accepted

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Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids.

Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I.

Nature Communications 10 ( 1 ) 4007 2019.09

Research paper (scientific journal), Joint Work, Accepted

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Preferential incorporation of administered eicosapentaenoic acid into thin-cap atherosclerotic plaques.

Sato T, Horikawa M, Takei S, Yamazaki F, Ito TK, Kondo T, Sakurai T, Kahyo T, Ikegami K, Sato S, Sato R, Jinno Y, Kawano H, Naoe S, Arita M, Kashiwagi Y, Setou M.

Arterioscler Thromb Vasc Biol 39 ( 9 ) 1802 - 1816 2019.09

Research paper (scientific journal), Joint Work, Accepted

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Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis

Miyata J., Fukunaga K., Kawashima Y., Watanabe T., Saitoh A., Hirosaki T., Araki Y., Kikawada T., Betsuyaku T., Ohara O., *Arita M.

Allergy: European Journal of Allergy and Clinical Immunology (Allergy: European Journal of Allergy and Clinical Immunology)  74 ( 6 ) 1113 - 1124 2019.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  01054538

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© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Eosinophils are multifunctional granulocytes capable of releasing various cytokines, chemokines, and lipid mediators. We previously reported dysregulated fatty acid metabolism in peripheral blood-derived eosinophils from patients with severe asthma. However, functional characteristics of eosinophils present in allergic inflammatory tissues remain largely uncharacterized. Methods: We established a method for isolating CD69hi CCR3low CXCR4- siglec-8int eosinophils from nasal polyps of patients with eosinophilic rhinosinusitis (NP-EOS). Multi-omics analysis including lipidomics, proteomics, and transcriptomics was performed to analyze NP-EOS as compared to peripheral blood-derived eosinophils from healthy subjects (PB-EOS). Results: Lipidomic analysis revealed impaired synthesis of prostaglandins and 15-lipoxygenase (15-LOX)-derived mediators, and selective upregulation of leukotriene D4 production. Furthermore, proteomics and transcriptomics revealed changes in the expression of specific enzymes (GGT5, DPEP2, and 15-LOX) responsible for dysregulated lipid metabolism. Ingenuity pathway analysis indicated the importance of type 2 cytokines and pattern recognition receptor pathways. Stimulation of PB-EOS with eosinophil activators IL-5, GM-CSF, and agonists of TLR2 and NOD2 mimicked the observed changes in lipid metabolism. Conclusion: Inflammatory tissue-derived eosinophils possess a specific phenotype with dysregulated fatty acid metabolism that may be targeted therapeutically to control eosinophilic inflammatory diseases.

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Proteogenomic Analyses of Cellular Lysates Using a Phenol-Guanidinium Thiocyanate Reagent

Kawashima Y., Miyata J., Watanabe T., Shioya J., Arita M., Ohara O.

Journal of Proteome Research (Journal of Proteome Research)  18 ( 1 ) 301 - 308 2019.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15353893

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© Copyright 2018 American Chemical Society. Protein and RNA profiles are highly informative when generating a comprehensive understanding of the dynamics of complex biological systems. Quantitative correlations between protein and RNA profiles are not always high, yet simultaneous acquisition of both profiles remains challenging, in part because of the limited availability of samples and the inconvenience of separately preparing protein and RNA fractions. In a previous study, protein, DNA, and RNA fractions were simultaneously prepared from the same sample using phenol-guanidinium isothiocyanate reagent (P/GTC), although the performance of P/GTC-extracts in proteogenomic analyses remains poorly understood. We therefore evaluated the performance of the P/GTC-extraction method in proteogenomic analyses using standard HEK293-F cells and human peripheral blood neutrophils. The latter cell type is renowned for its extreme vulnerability to protein/RNA degradation, reflecting high protease and RNase activities. Our data indicate that the P/GTC extraction method provides superior protein profiles from neutrophil and HEK293-F cell samples for simultaneous preparation of RNA and protein, as compared with those from conventional protein extraction methods. The P/GTC extraction method therefore provides a powerful and robust tool for a broad range of proteogenomic studies.

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Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

Imanishi T., Unno M., Kobayashi W., Yoneda N., Matsuda S., Ikeda K., Hoshii T., Hirao A., Miyake K., Barber G., Arita M., Ishii K., Akira S., Saito T.

Life Science Alliance (Life Science Alliance)  2 ( 1 ) e201800282 2019

Research paper (scientific journal), Joint Work, Accepted

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© 2019 Imanishi et al. Stimulator of interferon genes (STING) plays a key role in detecting cytosolic DNA and induces type I interferon (IFN-I) responses for host defense against pathogens. Although T cells highly express STING, its physiological role remains unknown. Here, we show that costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.

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Mass spectrometry data repository enhances novel metabolite discoveries with advances in computational metabolomics

Tsugawa H., Satoh A., Uchino H., Cajka T., Arita M., Arita M.

Metabolites (Metabolites)  9 ( 6 ) E119 2019

Research paper (scientific journal), Joint Work, Accepted

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© 2019 Metabolites. All rights reserved. Mass spectrometry raw data repositories, including Metabolomics Workbench and MetaboLights, have contributed to increased transparency in metabolomics studies and the discovery of novel insights in biology by reanalysis with updated computational metabolomics tools. Herein, we reanalyzed the previously published lipidomics data from nine algal species, resulting in the annotation of 1437 lipids achieving a 40% increase in annotation compared to the previous results. Specifically, diacylglyceryl-carboxyhydroxy-methylcholine (DGCC) in Pavlova lutheri and Pleurochrysis carterae, glucuronosyldiacylglycerol (GlcADG) in Euglena gracilis, and P. carterae, phosphatidylmethanol (PMeOH) in E. gracilis, and several oxidized phospholipids (oxidized phosphatidylcholine, OxPC; phosphatidylethanolamine, OxPE; phosphatidylglycerol, OxPG; phosphatidylinositol, OxPI) in Chlorella variabilis were newly characterized with the enriched lipid spectral databases. Moreover, we integrated the data from untargeted and targeted analyses from data independent tandem mass spectrometry (DIA-MS/MS) acquisition, specifically the sequential window acquisition of all theoretical fragment-ion MS/MS (SWATH-MS/MS) spectra, to increase the lipidomic annotation coverage. After the creation of a global library of precursor and diagnostic ions of lipids by the MS-DIAL untargeted analysis, the co-eluted DIA-MS/MS spectra were resolved in MRMPROBS targeted analysis by tracing the specific product ions involved in acyl chain compositions. Our results indicated that the metabolite quantifications based on DIA-MS/MS chromatograms were somewhat inferior to the MS1-centric quantifications, while the annotation coverage outperformed those of the untargeted analysis of the data dependent and DIA-MS/MS data. Consequently, integrated analyses of untargeted and targeted approaches are necessary to extract the maximum amount of metabolome information, and our results showcase the value of data repositories for the discovery of novel insights in lipid biology.

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Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection.

Codagnone M, Cianci E, Lamolinara A, Cecilia Mari V, Nespoli A, Arita M, Bragonzi A, Iezzi M, Romano M, *Recchiuti A.

Mucosal Immunol (Mucosal Immunology)  11 ( 1 ) 35 - 49 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  19330219

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Pseudomonas aeruginosa lung infection is a main cause of disability and mortality worldwide. Acute inflammation and its timely resolution are crucial for ensuring bacterial clearance and limiting tissue damage. Here, we investigated protective actions of resolvin (Rv) D1 in lung infection induced by the RP73 clinical strain of P. aeruginosa. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by RP73. Inoculum of RP73, immobilized in agar beads, resulted in persistent lung infection up to 21 days, leading to a non resolving inflammation reminiscent of human pathology. RvD1 significantly reduced bacterial titer, leukocyte infiltration, and lung tissue damage. In murine lung macrophages sorted during P. aeruginosa chronic infection, RvD1 regulated the expression of Toll-like receptors, downstream genes, and microRNA (miR)-21 and 155, resulting in reduced inflammatory signaling. In vitro, RvD1 enhanced phagocytosis of P. aeruginosa by neutrophils and macrophages, recapitulating its in vivo actions. These results unveil protective functions and mechanisms of action of RvD1 in acute and chronic P. aeruginosa pneumonia, providing evidence for its potent pro-resolution and tissue protective properties on airway mucosal tissue during infection.

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12-OH-17,18-epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs.

Mochimaru T, *Fukunaga K, Miyata J, Matsusaka M, Masaki K, Kabata H, Ueda S, Suzuki Y, Goto T, Urabe D, Inoue M, Isobe Y, Arita M, Betsuyaku T.

Allergy (Allergy: European Journal of Allergy and Clinical Immunology)  73 ( 2 ) 369 - 378 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  01054538

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© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

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Stereoselective total synthesis of macrophage-produced prohealing 14,21-dihydroxydocosahexaenoic acids.

Nishimura K, Sakaguchi T, Nanba Y, Suganuma Y, Morita M, Hong S, Lu Y, Jun B, Bazan NG, Arita M, *Kobayashi Y.

J Org Chem (Journal of Organic Chemistry)  83 ( 1 ) 154 - 166 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223263

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© 2017 American Chemical Society. Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr) 4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et 2 AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.

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Alveolar macrophages drive hepatocellular carcinoma lung metastasis by generating leukotriene B4.

Nosaka T, *Baba T, Tanabe Y, Sasaki S, Nishimura T, Imamura Y, Yurino H, Hashimoto S, Arita M, Nakamoto Y, Mukaida Y.

J Immunol (Journal of Immunology)  200 ( 5 ) 1839 - 1852 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00221767

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© 2018 by The American Association of Immunologists, Inc. All rights reserved. Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB 4 , augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB 4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB 4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB 4 .

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Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes.

Hata M, *Ikeda H, Iwai S, Iida Y, Gotoh N, Asaka I, Ikeda K, Isobe Y, Hori A, Nakagawa S, Yamato S, Arita M, Yoshimura N, Tsujikawa A.

Proc Natl Acad Sci USA (Proceedings of the National Academy of Sciences of the United States of America)  115 ( 15 ) 3936 - 3941 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00278424

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© 2018 National Academy of Sciences. All Rights Reserved. Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.

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Identification of protein targets of 12/15-lipoxygenase-derived lipid electrophiles in mouse peritoneal macrophages using omega-alkynyl fatty acid.

Isobe Y, Kawashima Y, Ishihara T, Watanabe K, Ohara O, *Arita M.

ACS Chem Biol (ACS Chemical Biology)  13 ( 4 ) 887 - 893 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15548929

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© 2018 American Chemical Society. The 12/15-lipoxygenase (12/15-LOX) enzyme introduces peroxyl groups, in a position-specific manner, into polyunsaturated fatty acids to form various kinds of bioactive lipid metabolites, including lipid-derived electrophiles (LDE). The resident peritoneal macrophage is the site of highest 12/15-LOX expression in the mouse. However, the role of the enzyme in the regulation of resident macrophages is not fully understood. Here, we describe a chemoproteomic method to identify the targets of enzymatically generated LDE. By treating mouse peritoneal macrophages with omega-alkynyl arachidonic acid (aAA), we identified a series of proteins adducted by LDE generated through a 12/15-LOX catalyzed reaction. Pathway analysis revealed a dramatic enrichment of proteins involved in energy metabolism and found that glycolytic flux and mitochondrial respiration were significantly affected by the expression of 12/15-LOX. Our findings thus highlight the utility of chemoproteomics using aAA for identifying intracellular targets of enzymatically generated LDE.

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Comprehensive analysis of the mouse cytochrome P450 family responsible for omega-3 epoxidation of eicosapentaenoic acid.

Isobe Y, Itagaki M, Ito Y, Naoe S, Kojima K, Ikeguchi M, *Arita M

Sci Rep (Scientific Reports)  8 ( 1 ) 7954 2018

Research paper (scientific journal), Joint Work, Accepted

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© 2018 The Author(s). Metabolites generated via oxygenation of the omega-3 double bond (omega-3 oxygenation) in eicosapentaenoic acid (EPA) have recently been identified as novel anti-inflammatory lipid mediators. Therefore, oxygenase(s) responsible for this metabolic pathway are of particular interest. We performed genome-wide screening of mouse cytochrome P450 (CYP) isoforms to explore enzymes involved in omega-3 oxygenation of EPA. As a result, 5 CYP isoforms (mouse Cyp1a2, 2c50, 4a12a, 4a12b, and 4f18) were selected and identified to confer omega-3 epoxidation of EPA to yield 17,18-epoxyeicosatetraenoic acid (17,18-EpETE). Stereoselective production of 17,18-EpETE by each CYP isoform was confirmed, and molecular modeling indicated that chiral differences stem from different EPA binding conformations in the catalytic domains of respective CYP enzymes.

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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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