Clarification of the mechanism of functional impairment of macrophages in sepsis and development of novel therapeutics

• Project/Area Number: 15K10523
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Tokai University
• Principal Investigator: WATANABE Nobuo 東海大学, 医学部, 助教 (80396928)
• Co-Investigator(Kenkyū-buntansha): 井上 茂亮 東海大学, 医学部, 准教授 (30582209)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 感染症 / 敗血症 / マクロファージ / 抗原提示 / 自己免疫疾患 / ハイスループットスクリーニング / 炎症

Outline of Final Research Achievements

Sepsis in elderly patients is associated initially with severe systemic inflammation, but later followed by immuno-suppressive state, which increases the risk of secondary infection. In this study we investigated the mechanism of sepsis-induced immuno-suppression and, based on the mechanism, aimed to established therapeutic strategy to reinstate impaired immune functions. Analysis of macrophages in mice with sepsis revealed that macrophages shifted to a low bactericidal phenotype (M2 type). Presentation by macrophages to T cells of antigenic peptide derived from phagocytosed bacteria is essential for mounting adaptive immune responses. We have established a screening assay system to select compounds that can facilitate antigenic peptide loading onto macrophages.

Research Products

• [Journal Article] Cha-Koji, comprising green tea leaves fermented with Aspergillus luchuensis var kawachii kitahara, increases regulatory T cell production in mice and humans (2018)
  • Author(s): Yamamoto Bunsei、Suzuki Yusuke、Yonezu Takahisa、Mizushima Nanami、Watanabe Nobuo、Sato Takehito、Inoue Shigeaki、Inokuchi Sadaki
  • Journal Title: Biosci Biotechnol Biochem Volume: 1 Issue: 5 Pages: 1-8
  • DOI: 10.1080/09168451.2018.1443789
  • Peer Reviewed
• [Journal Article] A cell-based high-throughput screening assay system for inhibitor compounds of antigen presentation by HLA class II molecule (2017)
  • Author(s): Watanabe Nobuo、Suzuki Yusuke、Yonezu Takahisa、Nakagawa Yuki、Shiina Takashi、Hirayama Noriaki、Inokuchi Sadaki、Inoue Shigeaki
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 6798-6798
  • DOI: 10.1038/s41598-017-07080-4
  • Peer Reviewed / Open Access
• [Journal Article] Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses (2017)
  • Author(s): Kawaguchi Ryoichi、Hirata Naoyuki、Tokinaga Yasuyuki、Hayashi Shunsuke、Inoue Shigeaki、Watanabe Nobuo、Yamakage Michiaki
  • Journal Title: Journal of Anesthesia Volume: 31 Issue: 6 Pages: 885-894
  • DOI: 10.1007/s00540-017-2417-0
  • NAID: 40021413831
  • Peer Reviewed
• [Journal Article] TGF-β-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche (2017)
  • Author(s): Yahata Takashi、Ibrahim Abd Aziz、Muguruma Yukari、Eren Mesut、Shaffer Alexander M.、Watanabe Nobuo、Kaneko Satoko、Nakabayashi Tetsuo、Dan Takashi、Hirayama Noriaki、Vaughan Douglas E.、Miyata Toshio、Ando Kiyoshi
  • Journal Title: Blood Volume: 130 Issue: 21 Pages: 2283-2294
  • DOI: 10.1182/blood-2017-02-767384
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sepsis induces incomplete M2 phenotype polarization in peritoneal exudate cells in mice (2016)
  • Author(s): Watanabe N, Suzuki Y, Inokuchi S, Inoue S
  • Journal Title: J Intensive Care Volume: 4 Issue: 1
  • DOI: 10.1186/s40560-015-0124-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Therapeutic potential of an orally effective small molecule inhibitor of plasminogen activator inhibitor for asthma (2016)
  • Author(s): Liu RM, Eldridge S, Watanabe N, Deshane J, Kuo HC, Jiang C, Wang Y, Liu G, Schwiebert L, Miyata T, Thannickal VJ
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 310(4） Issue: 4 Pages: L328-L336
  • DOI: 10.1152/ajplung.00217.2015
  • Peer Reviewed / Int'l Joint Research