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

iScience

Authors: Lisa U Teufel, Vasiliki Matzaraki, Lukas Folkman, Dennis M de Graaf, Rob Ter Horst, Simone J C F M Moorlag, Jéssica C Dos Santos, Catharina M Mulders-Manders, Thomas Krausgruber, Charles Dinarello, Mihai G Netea, Leo A B Joosten, Rob J W Arts

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 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 , 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 (IL-38KO mice) and (human monocytes). Our study therefore suggests that IL-38 endogenously regulates the induction of trained immunity in humans .

© 2025 The Author(s).

PMID: 41280669

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