Interleukin-38 is a Negative Regulator of Trained Immunity – a Retrospective Multi-omics Study
iScience, 2025
Teufel L., Matzaraki V., Folkman L., de Graaf D., Horst R., Moorlag S., dos Santos J., Mulders-Manders C., Krausgruber T., Dinarello C., Netea M., Joosten L., Arts R.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
Trained immunity is a long-lasting innate immune cell phenotype with benefits in infection control and recognised 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 regulator of trained immunity in vivo in a cohort of 325 healthy adults vaccinated with 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.