한빛사논문
Ji-Min Jua,1, Giri Nama,1, Young-Kwan Leea,b,1,2, Minho Junga, Hanna Changa, Woojin Kima, Woo Jeong Shonc, Ji Young Limd, Joo Young Kime, Jun Change, Chang Ki Mind, Dong-Sup Leea, Kyungho Choia, Dong-Mi Shinc,3, and Eun Young Choia,b,3
aDepartment of Biomedical Sciences, Seoul National University College of Medicine, Chongno-gu, 03080 Seoul, Korea; bInstitute of Human Environment Interface Biology, Seoul National University College of Medicine, Chongno-gu, 03080 Seoul, Korea; cDepartment of Food and Nutrition, Seoul National University College of Human Ecology, Gwanak-gu, 08826 Seoul, Korea; dDepartment of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seocho-gu, 06591 Seoul, Korea; and eDepartment of Pharmacy, Ewha University, Seodaemun-gu, 03760 Seoul, Korea
1J.-M.J., G.N., and Y.-K.L. contributed equally to this work.
2Present address: MJCellBio Co., Ltd., Deokyang-gu, Goyang-si, 10475 Gyonggi-do, Korea.
3To whom correspondence may be addressed.
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.
IDO, Gr-1+CD11b+ cell, myeloid-derived suppressor cell, ROS, GVHD
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