Acid ceramidase regulates innate immune memory

• Published in: Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113458-113458, Article 113458
• Main Authors: Rother, Nils, Yanginlar, Cansu, Prévot, Geoffrey, Jonkman, Inge, Jacobs, Maaike, van Leent, Mandy M.T., van Heck, Julia, Matzaraki, Vasiliki, Azzun, Anthony, Morla-Folch, Judit, Ranzenigo, Anna, Wang, William, van der Meel, Roy, Fayad, Zahi A., Riksen, Niels P., Hilbrands, Luuk B., Lindeboom, Rik G.H., Martens, Joost H.A., Vermeulen, Michiel, Joosten, Leo A.B., Netea, Mihai G., Mulder, Willem J.M., van der Vlag, Johan, Teunissen, Abraham J.P., Duivenvoorden, Raphaël
• Format: Article
• Language: English
• Subjects: acid ceramidase; Acid Ceramidase - genetics; Acid Ceramidase - metabolism; CP: Immunology; epigenetics; Histones; immune memory; Immunity, Innate; innate immunity; lipid metabolism; Lysine; monocytes; nanobiologics; sphingolipids; Sphingolipids - genetics; Trained Immunity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113458

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. [Display omitted] •Modulating sphingolipid metabolism affects the induction of trained immunity•Inhibition of acid ceramidase effectively suppresses trained immunity•Blocking acid ceramidase alters lipids, gene expression, and histone modifications•SNPs around ASAH1, encoding acid ceramidase, associate with trained immunity The sphingolipid metabolism is known to regulate cellular functions, including immune cell regulation. Rother et al. show that inhibition of acid ceramidase, a sphingolipid-converting enzyme, prevents the induction of trained immunity. This identifies an immunomodulatory function of sphingolipid metabolism in regulating the immunologic memory of innate immune cells.