Targeting Tryptophan Metabolism for Immune Regulation of Sepsis and Novel Therapeutic Strategies

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07432
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Fujita Health University
• Principal Investigator: Hoshi Masato 藤田医科大学, 保健学研究科, 准教授 (40633996)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: KMO / 3-hydroxykinurenine / Endotoxic shock / Interleukin-6 / ATF4 / Sepsis

Outline of Final Research Achievements

Despite advances in our understanding of endotoxic shock, novel therapeutic interventions that can reduce the burden of sepsis remain elusive. Current treatment options are limited, and it is only through refinements in the ways that we deliver supportive care that mortality has fallen over the years.
Here, the role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in LPS-induced endotoxemia using KMOKO and WT mice treated with the KMO inhibitor Ro61-8048. We showed that LPS-induced or cecal ligation and puncture-induced mortality and hepatic IL-6 production increased in the absence of KMO, possibly involving increased ATF4 signaling in hepatic macrophages. Moreover, treatment of septic mice with 3-hydroxykynurenine reduced mortality rates and inflammatory responses regardless of the presence or absence of KMO.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

抗菌薬の出現により細菌感染による死亡率は著しく減少したが、抗菌薬使用による耐性菌の問題やさらなる治療成績向上には、細菌を標的とする抗菌薬に加えて、生体側の免疫制御を標的とした新規治療戦略および検査法の確立が早急の課題である。
本研究では、マウス敗血症モデルにおけるKMOの役割を明らかにしたと共に、KMOの制御は耐性菌やさらなる治療効果の向上に向けた新規治療戦略となり得ることが期待された。