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

## 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.

## Key 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 monocytes). Our study therefore suggests that IL-38 endogenously regulates the induction of trained immunity in humans in vivo.

•IL-38 inhibits all hallmarks of trained immunity in humans•Plasma IL-38 concentrations regulate BCG-induced trained immunity in humans•IL-38 inhibits bone-marrow trained immunity in mice•IL-38 lowers trained immunity-based protection from fungal and parasitic infections

IL-38 inhibits all hallmarks of trained immunity in humans

Plasma IL-38 concentrations regulate BCG-induced trained immunity in humans

IL-38 inhibits bone-marrow trained immunity in mice

IL-38 lowers trained immunity-based protection from fungal and parasitic infections

Immunity; Immune response; Omics