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
  • 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: [email protected].
PMID: 35944460 DOI: 10.1016/j.intimp.2022.109098
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.
Products