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IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-03-09 , DOI: 10.1073/pnas.2011170118
Ji-Min Ju 1 , Giri Nam 1 , Young-Kwan Lee 1, 2 , Minho Jung 1 , Hanna Chang 1 , Woojin Kim 1 , Woo Jeong Shon 3 , Ji Young Lim 4 , Joo Young Kim 5 , Jun Chang 5 , Chang Ki Min 4 , Dong-Sup Lee 1 , Kyungho Choi 1 , Dong-Mi Shin 6 , Eun Young Choi 2, 7
Affiliation  

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.



中文翻译:

IDO1 清除髓源性抑制细胞中的活性氧以预防移植物抗宿主病 [免疫学和炎症]

色氨酸分解代谢酶吲哚胺 2,3-双加氧酶 1 (IDO1) 还具有免疫功能,可在炎症情况下抑制 T 细胞活化,包括移植物抗宿主病 (GVHD),这是同种异体骨髓移植(异基因移植)后的致命并发症。骨髓移植)。尽管 IDO1 的单核细胞表达与 GVHD 的改善结果相关,但潜在的机制仍不清楚。在此,我们使用 IDO 缺陷型 ( Ido1 -/- ) BMT 来了解为什么髓样 IDO 限制了 GVHD 的严重程度。带有Ido1 的主机-/-与野生型 (WT) allo-BMT 对照相比,BM 表现出更高的致死率,增强的促炎性和降低的调节性 T 细胞反应。尽管髓源性抑制细胞 (MDSC) 介质、精氨酸酶-1、诱导型一氧化氮合酶和白细胞介素 10 的表达相当,但来自同种异体BMT 或体外 BM 培养的Ido1 -/- Gr-1 + CD11b +细胞显示与 WT 对应物相比,免疫抑制功能受损,并倾向于 Ly6CLy6G hi子集。重要的是,Ido1 -/- Gr-1 + CD11b +细胞表现出升高水平的活性氧 (ROS) 和中性粒细胞数量。这些特征被具有完整血红素结合和催化活性的人类 IDO1 拯救,并通过用 IDO1 抑制剂 L1-甲基色氨酸处理 WT 细胞来重现。N-乙酰半胱氨酸清除 ROS将Ido1 -/- Gr-1 + CD11b +组成和功能恢复到 MDSC 状态,并提高了具有Ido1 -/- BM的 GVHD 宿主的存活率。总之,髓源性 IDO1 通过调节 ROS 水平和限制 Gr-1 + CD11b +的能力来提高 GVHD 存活率MDSCs 分化为促炎性中性粒细胞。我们的研究结果提供了对代谢酶 IDO1 免疫调节作用的机制洞察。

更新日期:2021-03-02
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