Interleukin-10 inhibits important components of trained immunity in human monocytes.

Trained immunity induces antigen-agnostic enhancement of host defense and protection against secondary infections, but inappropriate activation can contribute to the pathophysiology of inflammatory diseases. Tight regulation of trained immunity is therefore needed to avoid pathology, but little is known about the endogenous processes that modulate it. Here, we investigated the potential of interleukin (IL)-10, a prototypical anti-inflammatory cytokine, to inhibit trained immunity. IL-10 induced tolerance and inhibited trained immunity in primary human monocytes at both functional and transcriptional levels. Inhibition of STAT3, a signaling route that mediates IL-10 signals, induced trained immunity. IL-10 downregulated glycolytic and oxidative metabolism in monocytes but did not impact the metabolic effects of β-glucan-induced trained immunity. Furthermore, IL-10 prevented increased reactive oxygen species production in Bacillus Calmette-Guérin (BCG)-induced training but did not influence phagocytosis upregulation. In a cohort study of healthy volunteers vaccinated with BCG, genetic variants that influenced IL-10 or its receptor modulated BCG-induced trained immunity. Furthermore, circulating IL-10 concentrations were negatively correlated with induction of trained immunity after BCG vaccination in a sex-specific manner. In conclusion, IL-10 inhibited several, albeit not all, immunological functions amplified after induction of trained immunity. Follow-up studies should explore the precise molecular mechanism that mediates the effects of IL-10 on trained immunity. Addressing these knowledge gaps is an important step toward optimizing IL-10's potential as a therapeutic target in diseases characterized by inappropriate induction of trained immunity.