Exploration of early diagnosis for autoimmune hepatitis by combining lipid metabolism and liver dendritic cells.

• Project/Area Number: 17K08977
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Niigata University
• Principal Investigator: Tomiyama Chikako 新潟大学, 医歯学系, 准教授 (80359702)
• Co-Investigator(Kenkyū-buntansha): 尾関 百合子 新潟大学, 医歯学系, 助教 (00169301) ; 佐藤 英世 新潟大学, 医歯学系, 教授 (60235380)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 自己免疫性肝炎 / 樹状細胞 / 脂質 / 低エストロゲン / XCR1 / 総コレステロール / LDL-コレステロール / 卵巣摘出 / 肝臓 / pDC / cDC / 肝樹状細胞 / 脂質代謝異常 / 免疫学 / ストレス

Outline of Final Research Achievements

The purpose of this study was to clarify the relationship between immune tolerance disruption and onset of AIH through lipid metabolism and hepatic dendritic cells. In this study, ovariectomized and high fat diet-fed mice were used as a model of lipid metabolisms disorder. It was suggested that liver injury may be excerbated by a large amount of TNF-α producing hepatic CD11b+ cDCs in OVX mice induced AIH. On the other hand, it was observed that XCR-1+ cDCs accumulate in spleen of high-fat diet mice induced AIH. It was suggested that the mechanism of exacerbation of AIH in high fat diet-fed mice may be different from that in the ovariectomized model.

Academic Significance and Societal Importance of the Research Achievements

自己免疫疾患は免疫寛容の破綻が原因とされているがその発症については未だ解明されていないものが多い。自己免疫性肝炎についても同様であり、近年中年女性だけでなく男性患者の増加や診断時年齢の高齢化の報告もあることから、性差だけではない発症原因が予想される。今回、低エストロゲンモデルと実験的高脂血症モデルを用いて免疫応答を始動する樹状細胞の動態から発症原因を探索することは複雑化している発症原因と免疫寛容破綻との関連性を解明できるため、AIHだけでなく自己免疫性疾患の診断や治療法の基盤作成に貢献できると考えられる。

Research Products

• [Journal Article] Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity (2019)
  • Author(s): Loewen Jaycie L.、Albertini Giulia、Dahle E. Jill、Sato Hideyo、Smolders Ilse J.、Massie Ann、Wilcox Karen S.
  • Journal Title: Experimental Neurology Volume: 318 Pages: 50-60
  • DOI: 10.1016/j.expneurol.2019.04.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of Mild Hyperthermia Treatment Using Nano-Mist Sauna on Blood Gas Parameters and Skin Appearance (2018)
  • Author(s): Hayakawa Takayoshi、Watanabe Mayumi、Tomiyama Chikako、Sasagawa Ayaka、Honma Takashi、Inada Akihiro、Abo Toru
  • Journal Title: Health Volume: 10 Issue: 05 Pages: 577-586
  • DOI: 10.4236/health.2018.105046
  • Peer Reviewed / Open Access
• [Journal Article] The ferroptosis inducer erastin irreversibly inhibits system xc- and synergizes with cisplatin to increase cisplatin’s cytotoxicity in cancer cells. (2018)
  • Author(s): Sato, M., Kusumi, R., Hamashima, S., Kobayashi, S., Sasaki, S., Komiyama, Y., Izumikawa, T., Conrad, M., Bannai, S., and Sato. H.
  • Journal Title: Sci. Rep. Volume: 8 Issue: 1 Pages: 968-968
  • DOI: 10.1038/s41598-018-19213-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cystine/glutamate transporter, system x c- , is involved in nitric oxide production in mouse peritoneal macrophages (2018)
  • Author(s): Kobayashi S、Hamashima S、Homma T、Sato M、Kusumi R、Bannai S、Fujii J、Sato H
  • Journal Title: Nitric Oxide Volume: 78 Pages: 32-40
  • DOI: 10.1016/j.niox.2018.05.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Macrophages Switch Their Phenotype by Regulating Maf Expression during Different Phases of Inflammation (2018)
  • Author(s): Kikuchi Kenta、Iida Mayumi、Ikeda Naoki、Moriyama Shigetaka、Hamada Michito、Takahashi Satoru、Kitamura Hiroshi、Watanabe Takashi、Hasegawa Yoshinori、Hase Koji、Fukuhara Takeshi、Sato Hideyo、Kobayashi Eri H.、Suzuki Takafumi、Yamamoto Masayuki、Tanaka Masato、Asano Kenichi
  • Journal Title: The Journal of Immunology Volume: 201 Issue: 2 Pages: 635-651
  • DOI: 10.4049/jimmunol.1800040
  • Peer Reviewed / Open Access
• [Journal Article] Absence of system xc- on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. (2017)
  • Author(s): Merckx, E., Albertini, G., Paterka, M., Jensen, C., Albrecht, P., Dietrich, M., Liefferinge, J. V., Bentea, E., Verbruggen, L., Demuyser, T., Deneyer, L, Lewerenz, J., Loo, G. V., Keyser, J. D., Sato, H., Maher, P., Methner, A., and Massie, A.
  • Journal Title: J. Neuroinflam Volume: 14 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s12974-016-0787-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway (2017)
  • Author(s): Eun Sil Kang, Jaeyong Lee, Takujiro Homma, Toshihiro Kurahashi, Sho Kobayashi, Atsunori Nabeshima, Sohsuke Yamada, Han GeuK Seo, Satoshi Miyata, Hideyo Sato, Junichi Fujii
  • Journal Title: Free Radic Res Volume: 51 Issue: 1 Pages: 80-90
  • DOI: 10.1080/10715762.2017.1282157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zonisamide attenuates lactacystin-induced parkinsonism in mice without affecting system xc-. (2017)
  • Author(s): Bentea, E., Liefferinge, J. V., Verbruggen, L., Martens, K., Kobayashi, S., Deneyer, L., Demuyser, T., Albertini, G., Maes, K., Sato, H., Smolders, I., Lewerenz, J., and Massie, A.
  • Journal Title: Exp. Neurol. Volume: 290 Pages: 15-28
  • DOI: 10.1016/j.expneurol.2016.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of system xc- in methamphetamine-induced dopaminergic neurotoxicity in mice. (2017)
  • Author(s): Dang, D. K., Shin, E. J., Tran, H. Q., Kim, D. J., Jeong, J. H., Jang, C. G., Nah, S. Y., Sato, H., Nabeshima, T., Yoneda, Y., and Kim, H. C.
  • Journal Title: Neurochem. Int. Volume: 108 Pages: 254-265
  • DOI: 10.1016/j.neuint.2017.04.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased reproductive performance in xCT-knockout male mice. (2017)
  • Author(s): Hamashima, S., Homma, T., Kobayashi, S., Ishii, N., Kurahashi, T., Watanabe, R., Kimura, N., Sato, H., and Fujii, J.
  • Journal Title: Free Radic. Res. Volume: 51 Issue: 9-10 Pages: 851-860
  • DOI: 10.1080/10715762.2017.1388504
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The viability of primary hepatocytes in maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production. (2017)
  • Author(s): Lee, J., Kang, E. S., Kobayashi, S., Homma, T., Sato, H., Seo, H. G., and Fujii, J.
  • Journal Title: Exp. Cell Res. Volume: 361 Issue: 1 Pages: 178-191
  • DOI: 10.1016/j.yexcr.2017.10.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Exacerbation mechanisms of autoimmune hepatitis under low estrogen status and its relationship with hepatic dendritic cells. (2019)
  • Author(s): Tomiyama C, Hirama H, Yamamoto H, Watanabe H.
  • Organizer: The 26th International Symposium on Molecular Cell Biology of Macrophages (MMCB2019)
  • Int'l Joint Research
• [Presentation] Relationship between dendritic cell modulation and autoimmune hepatitis exacerbation during high fat feeding. (2019)
  • Author(s): Tomiyama C, Yamamoto H, Watanabe H.
  • Organizer: The 48th Annual Meeting of the Japanese Society for Immunology.
• [Presentation] The effects of a long-term repetitive mild hyperthermia treatment on the host defense mechanism and the autonomic nervous system. (2018)
  • Author(s): Tomiyama C, Watanabe M, Hayakawa T, Honma T.
  • Organizer: The 83rd Annual Meeting of the Japanese Society of Balneology, Climatoligy and Physical Medicine.
• [Presentation] Possible factors which exacerbate autoimmune hepatitis in low-level estrogen. (2018)
  • Author(s): Hirama H, Tomiyama C, Watanabe H, Yamamoto H.
  • Organizer: The 47th Annual Meeting of the Japanese Society for Immunology.
• [Presentation] The effects of ovariectomy on autoimmune hepatitis and hepatic dendritic cells. (2017)
  • Author(s): Hiroki HIRAMA, Chikako TOMIYAMA, Hisami WATANABE
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] シスチン/グルタミン酸輸送体は細胞内グルタチオンの維持を通じてがん細胞の遊走・浸潤・転移に寄与する (2017)
  • Author(s): 佐藤茉美、鈴木亜美、小沼邦重、尾崎充彦、坂内四郎、岡田太、佐藤英世
  • Organizer: ConBio2017生命科学系合同年次大会（第90回日本生化学会、第40回日本分子生物学会）
• [Presentation] ヒト由来骨肉腫細胞の浸潤能とグルタチオン合成系との関連性 (2017)
  • Author(s): 久住亮介、鈴木悠、小沼邦重、尾崎充彦、坂内四郎、岡田太、佐藤英世
  • Organizer: ConBio2017生命科学系合同年次大会（第90回日本生化学会、第40回日本分子生物学会）