OP0302 MUCOSAL-ASSOCIATED INVARIANT T (MAIT)-CELL-DERIVED IL-17A AND IL-17F PRODUCTION IS IL-23-INDEPENDENT AND BIASED TOWARDS IL-17F
by exposure to pathogens or vaccines, which evolved as a protective mechanism against infections. TI is characterized by rewiring of functional, epigenetic and metabolic programs of innate immune cells such as monocytes and macrophages, which sustain enhanced production of pro-inflammatory cytokines. Since aberrant activation of TI is implicated in inflammatory diseases, tight regulatory mechanisms are likely in place, but the mechanisms responsible for this modulation remain elusive.
... elusive. Objectives Scope of this study was to evaluated the role of IL-37, an anti-inflammatory cytokine that curbs inflammation as well as modulates metabolic pathways, as an endogenous regulator of trained immunity. Methods The effects of recombinant IL-37 were evaluated in a mouse model of TI induced by the administration of betaglucan in vivo (survival to a lethal inoculum of infectious agents, production of inflammatory cytokines, recruitment of inflammatory cells at the sites of infection). Subsequently, the effects of IL-37 were evaluated ex vivo on splenic and bone marrow monocytes (production of inflammatory cytokines, metabolomic analysis of the activation status of the main pathways of cellular energy metabolism). Finally, we evaluated the association between IL-37 gene polymorphisms and the induction of TI in monocytes of healthy donors with in vitro functional studies. Results The exogenous administration of IL-37 abrogates the pro-inflammatory effects of TI, significantly reducing the production of pro-inflammatory cytokines and the survival of experimental animals subjected to a disseminated infection model. The inhibitory effects of IL-37 on TI are also associated with reduced recruitment of neutrophils at sites of inflammation. IL-37 and TI programs have differential and opposite effects on the modulation of cellular energy metabolism of monocytes. In humans, polymorphisms in the IL-37 gene are associated with reduced activation of TI programs and reduced production of inflammatory cytokines by healthy donor monocytes. Conclusions In conclusion, IL-37 emerges as an endogenous regulator of TI, which makes this cytokine a potential therapeutic target in immune-mediated pathologies.