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  2. A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation

A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation

  • Int Immunopharmacol. 2022 Oct;111:109098. doi: 10.1016/j.intimp.2022.109098.
Yanxia Wei 1 Mengnan Liu 1 Jinzhi Han 1 Haohan Huang 1 Shihong Xu 1 Shenghan Zhang 1 Qiyue Jing 1 Hanying Wang 1 Huimin Bu 1 Yanbo Kou 1 Zhuanzhuan Liu 1 Kuiyang Zheng 1 Yugang Wang 2
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Immunity and Metabolism, Laboratory of Infection and Immunity, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 22104, China.
  • 2 Jiangsu Key Laboratory of Immunity and Metabolism, Laboratory of Infection and Immunity, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 22104, China. Electronic address: wangyg@xzhmu.edu.cn.
Abstract

The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. However, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflammation. Nitisinone (NTBC) is an orphan drug used to treat hereditary tyrosinemia type I potentially by changing Phe/Tyr metabolic flow. In this study, we used NTBC as a tool to investigate the potential role of the Phe/Tyr catabolic pathway in inflammatory responses. We found that NTBC was effective in tempering the Bacterial endotoxin lipopolysaccharide (LPS)-induced septic shock in mice. Mechanistically, the protective effect was related to the accumulation of a Phe/Tyr catabolic intermediate, 4-hydroxyphenylpyruvate (4-HPP), induced by the NTBC treatment. 4-HPP could inhibit NLRP3 inflammasome priming and activation processes and therefore reduce IL-1β release and Pyroptosis. Like NTBC, 4-HPP was also effective in attenuating endotoxic shock in mice. Our results suggest the Phe/Tyr catabolic pathway as a potential immunoregulatory hub that may be exploited therapeutically to alleviate inflammation.

Keywords

4-HPP, metabolism; IL-1β; Immunometabolism; Inflammasome; Macrophage; Pyroptosis.

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