2. Academic Validation
  3. Interleukin-38 is a negative regulator of trained immunity-A retrospective multi-omics study

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

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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