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 Gadina; Cornelia 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

doi:10.1038/s41467-021-24785-3

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

36 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 language	English
Article number	4447
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24785-3
State	Published - 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.

Funders	Funder number
National Institute on Aging	R01AG045223
National Institute of Arthritis and Musculoskeletal and Skin Diseases	ZIG AR041181-11
Division of Intramural Research, National Institute of Allergy and Infectious Diseases	AI137198
Horizon 2020 Framework Programme	667824 – EXCELLtoINNOV
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	310030_182528
Fondazione Telethon	GGP17094
Associazione Italiana per la Ricerca sul Cancro	19903
Sigrid Juséliuksen Säätiö	NIH-AI138552, T32 DK007110, AIRC 2019-23084, K12 GM102779/BETTR, NIH-AI103338

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10.1038/s41467-021-24785-3

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Clement, C. C., D’Alessandro, A., Thangaswamy, S., Chalmers, S., Furtado, R., Spada, S., Mondanelli, G., Ianni, F., Gehrke, S., Gargaro, M., Manni, G., Cara, L. C. L., Runge, P., Tsai, W. L., Karaman, S., Arasa, J., Fernandez-Rodriguez, R., Beck, A., Macchiarulo, A., ... Santambrogio, L. (2021). 3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine. Nature Communications, 12(1), Article 4447. https://doi.org/10.1038/s41467-021-24785-3

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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.",

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

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Clement, CC, D’Alessandro, A, Thangaswamy, S, Chalmers, S, Furtado, R, Spada, S, Mondanelli, G, Ianni, F, Gehrke, S, Gargaro, M, Manni, G, Cara, LCL, Runge, P, Tsai, WL, Karaman, S, Arasa, J, Fernandez-Rodriguez, R, Beck, A, Macchiarulo, A, Gadina, M, Halin, C, Fallarino, F, Skobe, M, Veldhoen, M, Moretti, S, Formenti, S, Demaria, S, Soni, RK, Galarini, R, Sardella, R, Lauvau, G, Putterman, C, Alitalo, K, Grohmann, U & Santambrogio, L 2021, '3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine', Nature Communications, vol. 12, no. 1, 4447. https://doi.org/10.1038/s41467-021-24785-3

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T1 - 3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine

AU - Clement, Cristina C.

AU - D’Alessandro, Angelo

AU - Thangaswamy, Sangeetha

AU - Chalmers, Samantha

AU - Furtado, Raquel

AU - Spada, Sheila

AU - Mondanelli, Giada

AU - Ianni, Federica

AU - Gehrke, Sarah

AU - Gargaro, Marco

AU - Manni, Giorgia

AU - Cara, Luisa Carlota Lopez

AU - Runge, Peter

AU - Tsai, Wanxia Li

AU - Karaman, Sinem

AU - Arasa, Jorge

AU - Fernandez-Rodriguez, Ruben

AU - Beck, Amanda

AU - Macchiarulo, Antonio

AU - Gadina, Massimo

AU - Halin, Cornelia

AU - Fallarino, Francesca

AU - Skobe, Mihaela

AU - Veldhoen, Marc

AU - Moretti, Simone

AU - Formenti, Silvia

AU - Demaria, Sandra

AU - Soni, Rajesh K.

AU - Galarini, Roberta

AU - Sardella, Roccaldo

AU - Lauvau, Gregoire

AU - Putterman, Chaim

AU - Alitalo, Kari

AU - Grohmann, Ursula

AU - Santambrogio, Laura

PY - 2021/7/21

Y1 - 2021/7/21

N2 - 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.

AB - 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.

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

Abstract

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Funding

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