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Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

ABSTRACT: Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologs in snake venoms (L-amino acid oxidases [LAAO]), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found that venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell protective gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.

SUBMITTER: Zeitler L

PROVIDER: S-EPMC7946422 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

Zeitler Leonie L Fiore Alessandra A Meyer Claudia C Russier Marion M Zanella Gaia G Suppmann Sabine S Gargaro Marco M Sidhu Sachdev S SS Seshagiri Somasekar S Ohnmacht Caspar C Köcher Thomas T Fallarino Francesca F Linkermann Andreas A Murray Peter J PJ

eLife 20210301

Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologs in snake venoms (L-amino acid oxidases [LAAO]), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found that venom LAAO kills cells via hydrogen peroxide gener ...[more]

PMID: 33646117

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Project description:The oxidoreductases interleukin 4-induced gene 1 (IL4I1) and L-Amino acid oxidase 1 (LAO) are known to catalyze L-amino acid metabolism, yet their physiological roles in intestinal homeostasis remain largely unexplored. In this study, we investigated the impact of IL4I1 and LAO1 deficiency on colonic inflammation by generating wild-type, single knockout (IL4I1 KO and LAO1 KO), and double knockout (DKO) mice. Notably, DKO mice exhibited spontaneous diarrhea and histologically confirmed colitis, which were absent or rare in the other genotypes. Transcriptomic profiling and qRT-PCR analyses revealed upregulated expression of pro-inflammatory cytokines (IL-6, IL-17, IFN-γ) and Th1/Th17 transcription factors, along with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon of DKO mice. Metabolomic analysis indicated elevated colonic kynurenine levels and impaired metabolism of L-phenylalanine, L-tyrosine, and L-tryptophan. These changes were associated with a significant reduction in hydrogen peroxide (H₂O₂) production. Furthermore, 16S rRNA gene sequencing revealed altered beta diversity and reduced abundance of Short-chain fatty acid-producing bacteria in DKO mice. Among short-chain fatty acids, pentanoate was significantly decreased in DKO cecal contents. Collectively, these findings suggest that IL4I1 and LAO1 are essential for maintaining intestinal immune and metabolic balance. Their combined deficiency disrupts L-amino acid metabolism and H₂O₂-mediated regulation of the IDO1–kynurenine pathway, ultimately promoting gut dysbiosis and inflammatory diarrhea. This study provides novel insights into the metabolic and microbial mechanisms underlying colonic inflammation and highlights IL4I1 and LAO1 as potential targets for therapeutic intervention in inflammatory bowel diseases. This study provides novel insights into the metabolic and microbial mechanisms underlying colonic inflammation and highlights IL4I1 and LAO1 as potential targets for therapeutic intervention in inflammatory bowel diseases.

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Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

Publications

Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism.

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