biostudies-literatureRother NEuropean Research CouncilRadboud Universitair Medisch CentrumNIDA NIH HHSNIAID NIH HHSNierstichtingDutch Research Council (NWO)Hartstichting113458https://www.ebi.ac.uk/biostudies/studies/S-EPMC11907240biostudies-literatureUnknown42(12)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 genCell reportsAcid ceramidase regulates innate immune memory.PMC11907240CVON2018-27R01 DA049547833247P01 AI168258van Leent MMTLindeboom RGHFayad ZAJacobs MVermeulen MMorla-Folch JJoosten LABMatzaraki VMartens JHAWang Wvan der Vlag JMulder WJMNetea MGRanzenigo AHilbrands LBRother NYanginlar Cvan Heck JAzzun ATeunissen AJPPrevot Gvan der Meel RDuivenvoorden RRiksen NPJonkman IfalseAcid ceramidase regulates innate immune memory.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 gen2023-01-01T00:00:00Z2023 Dec2026-06-01T05:45:32.808Z2025-04-04T00:09:01.765ZS-EPMC119072403799518410.1016/j.celrep.2023.113458