inhibition of inflammation and neutrophil function by voltage-gated proton channel Hv1/VSOP

• Project/Area Number: 15K08175
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Osaka University
• Principal Investigator: Yoshifumi Okochi 大阪大学, 医学系研究科, 助教 (90435818)
• Research Collaborator: Okamura Yasushi ; Umemoto Eiji
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プロトンチャネル / 炎症 / 好中球 / 走化性 / ERKシグナル / 活性酸素

Outline of Final Research Achievements

Voltage-gated proton channel, Hv1/VSOP, has a role to regulate neutrophil function and inhibit an inflammation in pathogen infection. Hv1/VSOP-deficient mice exhibit excess inflammation in lung after Candida infection. In this study, we found that Hv1/VSOP negatively regulates ROS production in neutrophils stimulated with low concentrations of fMLF. And, we demonstrated that this inhibitory function by Hv1/VSOP in ROS production is necessary for inhibiting ERK-dependent chemotactic response to low fMLF concentrations. These results may suggest that Hv1/VSOP inhibits an inflammation by suppressing neutrophil migration to infection site upon pathogen infection.

Academic Significance and Societal Importance of the Research Achievements

好中球は、感染時にいち早く感染部位に到着して病原菌を除去する役割を担う一方で、過剰な好中球の遊走は炎症を拡大させる負の側面を併せ持つ。そのため、好中球の遊走は適切にコントロールされる必要がある。我々は、電位依存性プロトンチャネルHv1/VSOP1が活性酸素の産生量を抑えることで低濃度の走化性因子に対する走化性応答を抑制することを明らかにした。この結果は、Hv1/VSOPが炎症の早期解決において好中球の遊走能を抑制する可能性を示唆する。今後、このHv1/VSOPの機能に着目した炎症をコントロールする方法の確立につながると期待される。

Research Products

• [Int'l Joint Research] Physiology & Experimental Medicine/Hospital for Sick Children(Canada)
• [Journal Article] Unconventional role of voltage-gated proton channels (VSOP/Hv1) in regulation of microglial ROS production (2017)
  • Author(s): Kawai Takafumi、Okochi Yoshifumi、Ozaki Tomohiko、Imura Yoshio、Koizumi Schuichi、Yamazaki Maya、Abe Manabu、Sakimura Kenji、Yamashita Toshihide、Okamura Yasushi
  • Journal Title: Journal of Neurochemistry Volume: 142 Issue: 5 Pages: 686-699
  • DOI: 10.1111/jnc.14106
  • Peer Reviewed / Open Access
• [Journal Article] リポクオリティによる膜タンパク質の機能制御と炎症・免疫～炎症抑制にかかわる電位依存性プロトンチャネルHv1/VSOPの機能 (2017)
  • Author(s): 大河内善史、川鍋陽、岡村康司
  • Journal Title: 炎症と免疫 Volume: 25 Pages: 17-22
• [Journal Article] The voltage-gated proton channel Hv1/VSOP inhibits neutrophil granule release (2016)
  • Author(s): Okochi Y, Aratani Y, Adissu HA, Miyawaki N, Sasaki M, Suzuki K, Okamura Y.
  • Journal Title: J Leukoc Biol. Volume: 99 Issue: 1 Pages: 7-19
  • DOI: 10.1189/jlb.3hi0814-393r
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Hv1/VSOP voltage-gated proton channel inhibits migration in response to fMLF in neutrophils (2019)
  • Author(s): Yoshifumi Okochi, Yasushi Okamura
  • Organizer: The 9th Federation of the Asian and Oceanian Physiological Societies Congress
  • Int'l Joint Research
• [Presentation] Measurement o f membrane potential change in phagosome of phagocytes (2018)
  • Author(s): Yoshifumi Okochi, Hidekazu Tsutsui and Yasushi Okamura
  • Organizer: 第95回日本生理学会大会
• [Presentation] Hv1/VSOP inhibits chemotaxis behavior toward fMLP in mouse neutrophils (2017)
  • Author(s): Yoshifumi Okochi and Yasushi Okamura
  • Organizer: The 94th Annual Meeting of The Physiological Society of Japan
  • Place of Presentation: Hamamatsu in shizuoka
  • Year and Date: 2017-03-28
• [Presentation] The role of voltage-gated proton channel Hv1 in neutrophil chemotaxis (2016)
  • Author(s): Yoshifumi Okochi and Yasushi Okamura
  • Organizer: The 93rd Annual Meeting of The Physiological Society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-22
• [Presentation] Voltage-gated proton channel Hv1/VSOP inhibits granule exocytosis in neutrophils and inflammation (2015)
  • Author(s): Yoshifumi Okochi, Yasuaki Aratani, Hibret A. Adissu, Nana Miyawaki, Mari Sasaki, Kazuo Suzuk, Yasushi Okamura
  • Organizer: 8th the Federation of the Asian and Oceanian Physiological Societies Congress
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-11-23
  • Int'l Joint Research
• [Remarks] 電位依存性プロトンチャネルHv1/VSOPは好中球の脱顆粒を抑制する
  • URL: http://physiology.jp/science-topic/17882/
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/phys2/okamura/