Elucidation of immune cell activation mechanism in the cholinergic anti-inflammatory pathway

• Project/Area Number: 19K21297
• Project/Area Number (Other): 18H06192 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0902:General internal medicine and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Inoue Tsuyoshi 東京大学, 医学部附属病院, 特任助教 (30821665)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 腎臓 / 迷走神経刺激 / マクロファージ / 急性腎障害

Outline of Research at the Start

炎症はさまざまな疾患の進展・増悪に深く関わっており，その制御は疾患の改善・予防に非常に重要である．最近の研究によって，神経系による免疫系の制御，なかでも迷走神経刺激を介した炎症の制御が，疾患の改善に寄与することが分かってきた．また，迷走神経刺激装置の臨床応用も関節リウマチや炎症性腸疾患などで進められている．そこで，本申請では，敗血症モデルおよび急性腎障害モデルを用いて，新規の抗炎症・臓器保護メカニズムの解明を目指す．

Outline of Final Research Achievements

We investigated the mechanism regarding the renal protection effect of vagus nerve stimulation,. Stimulating the vagus nerve releases acetylcholine from the nerve endings, and we showed that acetylcholine induces Hes1 gene expression through a specific receptor present in macrophages and improves renal injury. We also found that in a model of cisplatin-induced kidney injury that is often encountered in clinical practice, vagus nerve stimulation can reduce renal damage even after kidney injury has occurred.

Academic Significance and Societal Importance of the Research Achievements

多くの方が腎臓病を患う一方、腎臓病の根本的な治療法はいまだに存在せず、新たな治療法の開発は喫緊の課題である。本研究によって、神経系－免疫系を介した新規の腎臓保護作用メカニズムの一端を解明することができた。今後さらに研究を進めることで、腎臓病の新規の治療法開発につなげていきたい。

Research Products

• [Int'l Joint Research] バージニア大学(米国)
• [Int'l Joint Research] University of Virginia(米国)
• [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells (2020)
  • Author(s): Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
  • Journal Title: The EMBO Journal Volume: 39 Issue: 7 Pages: 1-1
  • DOI: 10.15252/embj.2019103949
  • NAID: 120006902140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Organelle crosstalk in the kidney (2019)
  • Author(s): Inoue Tsuyoshi、Maekawa Hiroshi、Inagi Reiko
  • Journal Title: Kidney International Volume: 印刷中 Issue: 6 Pages: 1318-1325
  • DOI: 10.1016/j.kint.2018.11.035
  • NAID: 40022012955
  • Peer Reviewed / Open Access
• [Journal Article] Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury (2019)
  • Author(s): Inoue Tsuyoshi、Tanaka Shinji、Rosin Diane L.、Okusa Mark D.
  • Journal Title: Cold Spring Harbor Perspectives in Medicine Volume: 9 Issue: 6 Pages: a034231-a034231
  • DOI: 10.1101/cshperspect.a034231
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroimmune interactions and kidney disease. (2019)
  • Author(s): Hasegawa S, Inoue T, Inagi R.
  • Journal Title: Kidney Res Clin Pract. Volume: 38 Issue: 3 Pages: 282-294
  • DOI: 10.23876/j.krcp.19.014
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury (2019)
  • Author(s): Hiroshi Maekawa, Tsuyoshi Inoue, haruki Ouchi, Tzu-Ming Jao, Reiko Inoue, Hiroshi Nishi, Rie Fujii, Fumiyoshi Ishidate, Tetsuhiro Tanaka, Yosuke Tanaka, Nobutaka Hirokawa, Masaomi Nangaku, Reiko Inagi
  • Journal Title: Cell Reports Volume: 29 Issue: 5 Pages: 1261-1273
  • DOI: 10.1016/j.celrep.2019.09.050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/ reperfusion injury in the kidney. (2019)
  • Author(s): Inoue T,Abe C, Kohro T, Tanaka S, Huang L, Yao J, Zheng S, Ye H, Inagi R, Stornetta RL, Rosin DL, Nangaku M, Wada Y, Okusa MD
  • Journal Title: Kidney International Volume: 95(3) Issue: 3 Pages: 563-576
  • DOI: 10.1016/j.kint.2018.09.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis (2019)
  • Author(s): Jao Tzu-Ming、Nangaku Masaomi、Wu Chia-Hsien、Sugahara Mai、Saito Hisako、Maekawa Hiroshi、Ishimoto Yu、Aoe Mari、Inoue Tsuyoshi、Tanaka Tetsuhiro、Staels Bart、Mori Kazutoshi、Inagi Reiko
  • Journal Title: Kidney International Volume: 95 Issue: 3 Pages: 577-589
  • DOI: 10.1016/j.kint.2018.09.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 神経系－免疫系を介した腎保護メカニズム (2020)
  • Author(s): 井上剛
  • Organizer: 第48回関東腎研究会
  • Invited
• [Presentation] Neuro-immune axis on kidney disease (2020)
  • Author(s): 井上剛
  • Organizer: 第97回日本生理学会大会
  • Invited
• [Presentation] 急性腎障害における脳腎連関 (2019)
  • Author(s): 井上剛
  • Organizer: 第62回日本腎臓学会学術大会
  • Invited
• [Presentation] 腎障害における神経系と免疫系の関連 (2019)
  • Author(s): 井上剛
  • Organizer: 第28回日本病態生理学会大会
  • Invited
• [Presentation] Renal protective effect through nervous and immune systems (2019)
  • Author(s): 井上剛
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] 急性腎障害における神経系-免疫系の関連 (2019)
  • Author(s): 井上剛
  • Organizer: 第49回日本腎臓学会西部学術大会
  • Invited
• [Presentation] Neural-renal linkage through the immune system (2019)
  • Author(s): 井上剛
  • Organizer: 第42回日本分子生物学学会年会
  • Invited