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

Affiliation

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]

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.