Interleukin-38 is a negative regulator of trained immunity—A retrospective multi-omics study
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 <i>in vivo</i> 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 <i>IL1F10</i>, 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 <i>in vivo</i> (IL-38KO mice) and <i>in vitro</i> (human monocytes). Our study therefore suggests that IL-38 endogenously regulates the induction of trained immunity in humans <i>in vivo</i>.
Authors
- Jéssica Cristina dos Santos (ORCID: https://orcid.org/0000-0001-9191-7356)
- Lisa U. Teufel (ORCID: https://orcid.org/0000-0003-4287-5908)
- Simone J.C.F.M. Moorlag (ORCID: https://orcid.org/0000-0001-8884-8417)
- Vasiliki Matzaraki (ORCID: https://orcid.org/0000-0002-5852-6801)
- Rob ter Horst (ORCID: https://orcid.org/0000-0003-0576-5873)
- Charles A. Dinarello (ORCID: https://orcid.org/0000-0002-5073-8316)
- Leo A. B. Joosten (ORCID: https://orcid.org/0000-0001-6166-9830)
- Thomas Krausgruber (ORCID: https://orcid.org/0000-0002-1374-0329)
- Rob J.W. Arts (ORCID: https://orcid.org/0000-0002-6649-7190)
- Lukas Folkman (ORCID: https://orcid.org/0000-0002-5811-8875)
- Dennis M. de Graaf (ORCID: https://orcid.org/0000-0002-9198-7159)
- Catharina M Mulders-Manders
- Mihai G. Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
Institutions
- University of Bonn (DE)
- Austrian Academy of Sciences (AT)
- Radboud University Nijmegen (NL)
- Austrian Research Institute for Artificial Intelligence (AT)
- Iuliu Hațieganu University of Medicine and Pharmacy (RO)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- CeMM Research Center for Molecular Medicine (AT)
- University of Colorado Anschutz Medical Campus (US)
- Medical University of Vienna (AT)
- University of Colorado Denver (US)
Publication Details
- Journal
- iScience
- Published
- 2025-10-15
- DOI
- https://doi.org/10.1016/j.isci.2025.113758
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Österreichischen Akademie der Wissenschaften
- Universität Wien
- Medizinische Universität Wien
- National Institutes of Health
- H2020 Marie Skłodowska-Curie Actions