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^lowLy6G^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.

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 Ly6C^低Ly6G ^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。