Interleukin-38 is a negative regulator of trained immunity-A retrospective multi-omics study

  • iScience. 2025 Oct 14;28(11):113758. doi: 10.1016/j.isci.2025.113758.
Lisa U Teufel  1 ,  Vasiliki Matzaraki  2 ,  Lukas Folkman  3  4 ,  Dennis M de Graaf  5  6 ,  Rob Ter Horst  3  4 ,  Simone J C F M Moorlag  2 ,  Jéssica C Dos Santos  2 ,  Catharina M Mulders-Manders  2 ,  Thomas Krausgruber  3  4 ,  Charles Dinarello  5 ,  Mihai G Netea  2  7 ,  Leo A B Joosten  2  8 ,  Rob J W Arts  2
Affiliations
  • 1. Department of Medical BioSciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 2. Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 3. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 4. Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria.
  • 5. Department of Medicine, University of Colorado, Aurora, CO 80045, USA.
  • 6. Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • 7. Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • 8. Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania.
PMID: 41280669 DOI: 10.1016/j.isci.2025.113758
Abstract

Trained immunity is a long-lasting innate immune cell phenotype with benefits in Infection control and recognized anti-cancer effects. Conversely, inappropriately induced trained immunity contributes to pathological inflammation, warranting the exploration of regulatory pathways. We explore interleukin-38 (IL-38) as a regulator of trained immunity in vivo in a cohort of 325 healthy adults vaccinated with Bacillus Calmette-Guérin (BCG). Using multi-omics profiling, we find that IL-38 is negatively associated with trained immunity on metabolic and epigenetic level. Genetic variants in IL1F10, encoding for IL-38, further link IL-38 to diminished training responses. These associations were validated in human and murine models. We confirmed that IL-38 functionally impairs anti-microbial traits of trained immunity in trained immunity-infection models in vivo (IL-38KO mice) and in vitro (human monocytes). Our study therefore suggests that IL-38 endogenously regulates the induction of trained immunity in humans in vivo.

Keywords
Immune response; Immunity; Omics.
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