| First Author | Ju JM | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 10 | PubMed ID | 33649207 |
| Mgi Jnum | J:337047 | Mgi Id | MGI:6511159 |
| Doi | 10.1073/pnas.2011170118 | Citation | Ju JM, et al. (2021) IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease. Proc Natl Acad Sci U S A 118(10) |
| abstractText | 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 Ly6C(low)Ly6G(hi) 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. |
