文章基本信息

标题：IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease
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作者：Ji-Min Ju ; Giri Nam ; Young-Kwan Lee 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：10
页码：1
DOI：10.1073/pnas.2011170118
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：IDO ; Gr-1 CD11b cell ; myeloid-derived suppressor cell ; ROS ; GVHD