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

Cited 17 time in Web of Science Cited 18 time in Scopus
Authors

Ju, Ji-Min; Nam, Giri; Lee, Young-Kwan; Jung, Minho; Chang, Hanna; Kim, Woojin; Shon, Woo Jeong; Lim, Ji Young; Kim, Joo Young; Chang, Jun; Min, Chang Ki; Lee, Dong-Sup; Choi, Kyungho; Shin, Dong-Mi; Choi, Eun Young

Issue Date
2021-03-09
Publisher
National Academy of Sciences
Citation
Proceedings of the National Academy of Sciences of the United States of America, Vol.118 No.10, p. e2011170118
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 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.
ISSN
0027-8424
URI
https://hdl.handle.net/10371/190057
DOI
https://doi.org/10.1073/pnas.2011170118
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