2. Academic Validation
  3. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory

Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory

  • Cell. 2025 May 29;188(11):2992-3012.e16. doi: 10.1016/j.cell.2025.03.048.
Athanasios Ziogas 1,  Boris Novakovic 2,  Lorenzo Ventriglia 3,  Noriko Galang 4,  Kim A Tran 5,  Wenchao Li 6,  Vasiliki Matzaraki 7,  Nienke van Unen 6,  Titus Schlüter 7,  Anaísa V Ferreira 7,  Simone J C F M Moorlag 7,  Valerie A C M Koeken 8,  Mthabisi Moyo 9,  Xiaolin Li 9,  Marijke P A Baltissen 10,  Joost H A Martens 10,  Yang Li 11,  Maziar Divangahi 5,  Leo A B Joosten 12,  Musa M Mhlanga 9,  Mihai G Netea 13
Affiliations

Affiliations

  • 1 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Cell Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands. Electronic address: athanasios.ziogas@radboudumc.nl.
  • 2 Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia.
  • 3 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Hepatogastroenterology Division, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • 4 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Cell Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands.
  • 5 Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, Research Institute of the McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada.
  • 6 Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
  • 7 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 8 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, the Netherlands.
  • 9 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Cell Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 10 Department of Molecular Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, the Netherlands.
  • 11 Department of Computational Biology of Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hanover Medical School, Hannover, Germany; Lower Saxony center for artificial intelligence and causal methods in medicine (CAIMed), Hannover, Germany.
  • 12 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
  • 13 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. Electronic address: mihai.netea@radboudumc.nl.
PMID: 40318634 DOI: 10.1016/j.cell.2025.03.048
Abstract

Trained immunity, a de facto innate immune memory characterized by enhanced responsiveness to future challenges, is underpinned by epigenetic and metabolic rewiring. In individuals vaccinated with Bacille Calmette-Guérin (BCG), lactate release was associated with enhanced cytokine responsiveness upon restimulation. Trained monocytes/macrophages are characterized by lactylation of histone H3 at lysine residue 18(H3K18la), mainly at distal regulatory regions. Histone lactylation was positively associated with active chromatin and gene transcription, persisted after the elimination of the training stimulus, and was strongly associated with "trained" gene transcription in response to a secondary stimulus. Increased lactate production upon induction of trained immunity led to enhanced production of proinflammatory cytokines, a process associated with histone lactylation. Pharmacological inhibition of lactate production or histone lactylation blocked trained immunity responses, while polymorphisms of LDHA and EP300 genes modulated trained immunity. Long-term histone lactylation persisted in vivo 90 days after vaccination with BCG, highlighting H3K18la as an epigenetic MARK of innate immune memory.

Keywords

BCG; Bacillus Calmette-Guérin; H3K18la; lactate; lactylation; trained immunity.

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