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 () and Laura Santambrogio ()
Additional contact information
Cristina C. Clement: Weill Cornell Medicine
Angelo D’Alessandro: University of Colorado Denver, Anschutz Medical Campus
Sangeetha Thangaswamy: Weill Cornell Medicine
Samantha Chalmers: Albert Einstein College of Medicine
Raquel Furtado: Albert Einstein College of Medicine
Sheila Spada: Weill Cornell Medicine
Giada Mondanelli: University of Perugia
Federica Ianni: University of Perugia
Sarah Gehrke: University of Colorado Denver, Anschutz Medical Campus
Marco Gargaro: University of Perugia
Giorgia Manni: University of Perugia
Luisa Carlota Lopez Cara: University of Granada
Peter Runge: Institute of Pharmaceutical Sciences, ETH Zurich
Wanxia Li Tsai: Translational Immunology Section, National Institute of Arthritis Musculoskeletal and Skin Diseases
Sinem Karaman: University of Helsinki
Jorge Arasa: Institute of Pharmaceutical Sciences, ETH Zurich
Ruben Fernandez-Rodriguez: Icahn School of Medicine at Mount Sinai
Amanda Beck: Albert Einstein College of Medicine
Antonio Macchiarulo: University of Perugia
Massimo Gadina: Translational Immunology Section, National Institute of Arthritis Musculoskeletal and Skin Diseases
Cornelia Halin: Institute of Pharmaceutical Sciences, ETH Zurich
Francesca Fallarino: University of Perugia
Mihaela Skobe: Icahn School of Medicine at Mount Sinai
Marc Veldhoen: Faculdade de Medicina da Universidade de Lisboa
Simone Moretti: Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati”
Silvia Formenti: Weill Cornell Medicine
Sandra Demaria: Weill Cornell Medicine
Rajesh K. Soni: Columbia University Irving Medical Center
Roberta Galarini: Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati”
Roccaldo Sardella: University of Perugia
Gregoire Lauvau: Albert Einstein College of Medicine
Chaim Putterman: Albert Einstein College of Medicine
Kari Alitalo: University of Helsinki
Ursula Grohmann: University of Perugia
Laura Santambrogio: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24785-3

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