Ju JM(1), Nam G(1), Lee YK(1)(2), Jung M(1), Chang H(1), Kim W(1), Shon WJ(3), Lim JY(4), Kim JY(5), Chang J(5), Min CK(4), Lee DS(1), Choi K(1), Shin DM(6), Choi EY(7)(2). Author information:
(1)Department of Biomedical Sciences, Seoul National University College of
Medicine, Chongno-gu, 03080 Seoul, Korea.
(2)Institute of Human Environment Interface Biology, Seoul National University
College of Medicine, Chongno-gu, 03080 Seoul, Korea.
(3)Department of Food and Nutrition, Seoul National University College of Human
Ecology, Gwanak-gu, 08826 Seoul, Korea.
(4)Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic
University of Korea, Seocho-gu, 06591 Seoul, Korea.
(5)Department of Pharmacy, Ewha University, Seodaemun-gu, 03760 Seoul, Korea.
(6)Department of Food and Nutrition, Seoul National University College of Human
Ecology, Gwanak-gu, 08826 Seoul, Korea; [Email] [Email]
(7)Department of Biomedical Sciences, Seoul National University College of
Medicine, Chongno-gu, 03080 Seoul, Korea; [Email] [Email]
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.
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