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IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease
- Title
- IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease
- Authors
- Ju J.-M.; Nam G.; Lee Y.-K.; Jung M.; Chang H.; Kim W.; Shon W.J.; Lim J.Y.; Kim J.Y.; Chang J.; Min C.K.; Lee D.-S.; Choi K.; Shin D.-M.; Choi E.Y.
- Ewha Authors
- 장준
- SCOPUS Author ID
- 장준
- Issue Date
- 2021
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- ISSN
- 0027-8424
- Citation
- Proceedings of the National Academy of Sciences of the United States of America vol. 118, no. 10
- Keywords
- Gr-1+CD11b+ cell; GVHD; IDO; Myeloid-derived suppressor cell; ROS
- Publisher
- National Academy of Sciences
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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. © 2021 National Academy of Sciences. All rights reserved.
- DOI
- 10.1073/pnas.2011170118
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
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