3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine

Cristina C. Clement, Angelo D’Alessandro, Sangeetha Thangaswamy, Samantha Chalmers, Raquel Furtado, Sheila Spada, Giada Mondanelli, Federica Ianni, Sarah Gehrke, Marco Gargaro, Giorgia Manni, Luisa Carlota Lopez Cara, Peter Runge, Wanxia Li Tsai, Sinem Karaman, Jorge Arasa, Ruben Fernandez-Rodriguez, Amanda Beck, Antonio Macchiarulo, Massimo GadinaCornelia Halin, Francesca Fallarino, Mihaela Skobe, Marc Veldhoen, Simone Moretti, Silvia Formenti, Sandra Demaria, Rajesh K. Soni, Roberta Galarini, Roccaldo Sardella, Gregoire Lauvau, Chaim Putterman, Kari Alitalo, Ursula Grohmann, Laura Santambrogio

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.

Original languageEnglish
Article number4447
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - 21 Jul 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

The work was supported by the following grants: NIH-AG045223 and NIH-AI137198 to L.S.; the Swiss National Science Foundation, grant 310030_182528 to C.H.; Telethon GGP17094 and the Associazione Italiana per la Ricerca sul Cancro (AIRC; 19903) to F.F.; Sigrid Juselius Foundation to K.A.; NIH T32 DK007110 to S.C.; NIH-AI103338 and NIH-AI138552 to G.L.; NIH K12 GM102779/BETTR program to R.F.; Associazione Italiana per la Ricerca sul Cancro (AIRC 2019-23084) to U.G.; The Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIG AR041181-11) to W.L.T. and M.G. European Union H2020 ERA project (No. 667824 – EXCELLtoINNOV) to M.V.

FundersFunder number
National Institute on AgingR01AG045223
National Institute of Arthritis and Musculoskeletal and Skin DiseasesZIG AR041181-11
Division of Intramural Research, National Institute of Allergy and Infectious DiseasesAI137198
Horizon 2020 Framework Programme667824 – EXCELLtoINNOV
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung310030_182528
Fondazione TelethonGGP17094
Associazione Italiana per la Ricerca sul Cancro19903
Sigrid Juséliuksen SäätiöNIH-AI138552, T32 DK007110, AIRC 2019-23084, K12 GM102779/BETTR, NIH-AI103338

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