IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease

Abstract

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1−/−) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1−/− BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1−/− Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1−/−Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1−/−Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1−/− BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

MDSC in Mice and Men: Mechanisms of Immunosuppression in Cancer

“…IDO-KO mice lack functional MDSCs compared to WT specimens in a model of graft versus host disease [108]. However, direct evidence of IDO expression in M-or PMN-MDSCs is still lacking.…”

Structure and Plasticity of Indoleamine 2,3-Dioxygenase 1 (IDO1)

“…Novel aspects of IDO1 biology that potentially influence its role as drug target in cancer, infectious diseases, autoimmunity, and neurodegeneration continue to be discovered, such as its regulation by heme availability, 13 its activation by polysulfides, 14 its nitrite reductase activity, 15 its involvement in the redox signaling pathways of hydrogen peroxide and singlet oxygen, 16,17 and its reactive oxygen species scavenging activity. 18 Therefore, there is an ongoing interest in IDO1's biology and pharmacological inhibitors capable of modulating these different pathways and processes.…”

“…IDO1’s interaction sites with Src homology 2 domain phosphatases (SHPs), phosphoinositide 3-kinases (PI3Ks), and suppressor of cytokine signaling 3 (SOCS3) are all localized in the small domain and are distinct from the enzymatic active site in the large domain (Figure A). Novel aspects of IDO1 biology that potentially influence its role as drug target in cancer, infectious diseases, autoimmunity, and neurodegeneration continue to be discovered, such as its regulation by heme availability, its activation by polysulfides, its nitrite reductase activity, its involvement in the redox signaling pathways of hydrogen peroxide and singlet oxygen, , and its reactive oxygen species scavenging activity . Therefore, there is an ongoing interest in IDO1’s biology and pharmacological inhibitors capable of modulating these different pathways and processes.…”

Immune-Related Genes for Predicting Future Kidney Graft Loss: A Study Based on GEO Database

“…Several previous studies have demonstrated the protective role of IDO1 in graft-versus-host disease (GVHD) (30,31). A recent study suggested that myeloid-derived IDO1 had the ability to improve GVHD survival (32). GBP2 was a commonly used gene that distinguished non-rejection and rejection kidney allografts (33).…”