IDO1 Inhibitor RY103 Prevents Sepsis-Associated Immunosuppression in Cecal Ligation and Puncture Mice

Prolonged immunosuppression is a major risk factor for sepsis death. The mechanism of sepsis-associated immunosuppression remains unclear, hindering timely and targeted immunotherapy. The immunomodulatory enzyme, indoleamine-2,3-dioxygenase 1 (IDO1), is overactivated in patients with sepsis; however, its role in sepsis-associated immunosuppression remains unclear. In this study, we defined the time window when cecal ligation puncture (CLP) mice, a gold-standard sepsis model, entered the immunosuppressive state and confirmed elevated IDO1 activity during this phase. The IDO1 inhibitor prevented the occurrence of immunosuppression in CLP mice by decreasing the concentration of interleukin-10 (IL-10), the number of regulatory T cells and myeloid-derived suppressor cells, and increasing the proportion of M1 macrophages, which led to clearance of pathogenic bacteria in the peritoneal cavity. The IDO1 inhibitor enhanced resistance to infection and improved the survival of septic mice during secondary infection with Staphylococcus aureus . Finally, we explored the potential role of IDO1 in macrophages, key participants in the progression of sepsis. IDO1 preferentially promoted IL-10 production in septic macrophages through the aryl hydrocarbon receptor–STAT3 axis. In macrophages, IDO1 inhibited the mammalian target of rapamycin pathway by depleting ambient tryptophan, leading to the downregulation of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the metabolic reprogramming mediator hypoxia-inducible factor 1-alpha (HIF-1α). The downregulation of PGC-1α and HIF-1α inhibited mitochondrial biogenesis and glycolysis, respectively, both of which were essential for immune defense. These results demonstrate that IDO1 is a crucial mediator of sepsis-associated immunosuppression, and that targeting IDO1 could serve as a therapeutic strategy for sepsis.