Cell Reports (Dec 2023)
Acid ceramidase regulates innate immune memory
- Nils Rother,
- Cansu Yanginlar,
- Geoffrey Prévot,
- Inge Jonkman,
- Maaike Jacobs,
- Mandy M.T. van Leent,
- Julia van Heck,
- Vasiliki Matzaraki,
- Anthony Azzun,
- Judit Morla-Folch,
- Anna Ranzenigo,
- William Wang,
- Roy van der Meel,
- Zahi A. Fayad,
- Niels P. Riksen,
- Luuk B. Hilbrands,
- Rik G.H. Lindeboom,
- Joost H.A. Martens,
- Michiel Vermeulen,
- Leo A.B. Joosten,
- Mihai G. Netea,
- Willem J.M. Mulder,
- Johan van der Vlag,
- Abraham J.P. Teunissen,
- Raphaël Duivenvoorden
Affiliations
- Nils Rother
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Cansu Yanginlar
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Geoffrey Prévot
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Inge Jonkman
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Maaike Jacobs
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Mandy M.T. van Leent
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, the Netherlands
- Julia van Heck
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
- Vasiliki Matzaraki
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
- Anthony Azzun
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Judit Morla-Folch
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Anna Ranzenigo
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- William Wang
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Roy van der Meel
- Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
- Zahi A. Fayad
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Niels P. Riksen
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands
- Luuk B. Hilbrands
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Rik G.H. Lindeboom
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands
- Joost H.A. Martens
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands
- Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Oncode Institute, Radboud University Nijmegen, Nijmegen, the Netherlands
- Leo A.B. Joosten
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, University of Medicine and Pharmacy, Iuliu Haţieganu, Cluj-Napoca, Romania
- Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- Willem J.M. Mulder
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
- Johan van der Vlag
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands
- Abraham J.P. Teunissen
- Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Raphaël Duivenvoorden
- Department of Nephrology, Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands; Biomolecular Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 12
p. 113458
Abstract
Summary: Innate immune memory, also called ''trained immunity,'' is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.
