A tyrosine catabolic intermediate 4-hydroxyphenylpyruate attenuates murine endotoxic shock by blocking NLRP3 inflammasome activation
International Immunopharmacology(2022)
摘要
The metabolic alterations of amino acid metabolism are closely associated with inflammatory response. How-ever, relatively little is known about the roles of phenylalanine (Phe)/tyrosine (Tyr) catabolites during inflam-mation. 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-1 beta 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.
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关键词
Inflammasome,Pyroptosis,4-HPP metabolism,Macrophage,IL-1?,Immunometabolism
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