Interleukin-38 is a negative regulator of trained immunity—A retrospective multi-omics study
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
TL;DR
This study shows that IL-38 reduces trained immunity in humans and mice, affecting infection protection and immune responses.
Contribution
The study identifies IL-38 as a negative regulator of trained immunity through multi-omics and experimental validation.
Findings
IL-38 inhibits all hallmarks of trained immunity in humans.
IL-38 lowers trained immunity-based protection from fungal and parasitic infections.
Genetic variants in IL1F10 link IL-38 to diminished training responses.
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…
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Taxonomy
TopicsImmune responses and vaccinations · Immune Cell Function and Interaction · IL-33, ST2, and ILC Pathways