Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?
Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?
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DOI：
10.3389/fimmu.2017.01360
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发表时间：
2017
影响因子：
7.3
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Mellor AL;Lemos H;Huang L
表达IDO的细胞通过分解代谢氨基酸色氨酸（Trp）和其他吲哚化合物来抑制先天性和适应性免疫以促进耐受性。在炎症部位或由活化的免疫细胞产生的I型干扰素（IFN-I）和II型干扰素（IFN-II）是有效的IDO诱导剂，因为哺乳动物IDO基因含有IFN应答元件。树突状细胞（DC）的升高的IDO表达具有特别重要的意义，因为IDO活性将成熟DC转化成致耐受性APC，其抑制效应T细胞（Teff）并促进调节性T细胞（Teff），从而促进耐受性。局部Trp耗竭和免疫抑制性Trp催化剂的产生通过激活分别响应于氨基酸戒断和芳烃信号传导的代谢途径而有助于致耐受性过程。持续的IDO升高产生局部免疫豁免，其保护组织免受免疫介导的损伤并允许组织愈合。这种反应发生在淋巴组织中，当死亡的组织细胞释放的DNA被感知以诱导特化的DC亚群获得致耐受性表型时。IDO的致耐受性作用还促进肿瘤发生并帮助在癌症中建立免疫检查点，因为恶性细胞受到保护免受免疫监视。类似的过程可能会减弱宿主对某些病原体的免疫力，这些病原体在免疫活性个体中持续存在。然而，如果IDO参与的炎症没有得到解决，这些部位的慢性免疫激活会随着时间的推移导致进行性组织损伤。持续IDO活性的另一个作用是增强疼痛敏感性，因为由表达IDO的细胞产生的一些Trp催化剂是神经活性的。在这篇综述中，我们总结了IDO和慢性炎症性疾病之间的联系，并讨论了利用IDO和色氨酸催化剂抑制免疫和促进耐受性的临床益处，特别强调保护组织免受破坏性自身免疫的前景。
Cells expressing IDO suppress innate and adaptive immunity to promote tolerance by catabolizing the amino acid tryptophan (Trp) and other indole compounds. Interferon type I (IFN-I) and type II (IFN-II) produced at sites of inflammation or by activated immune cells are potent IDO inducers because mammalian IDO genes contain IFN response elements. Elevated IDO expression by dendritic cells (DCs) is of particular significance because IDO activity converts mature DCs into tolerogenic APCs that suppress effector T cells (Teff) and promote regulatory T cells (Tregs), thereby promoting tolerance. Local Trp depletion and production of immune suppressive Trp catabolites contribute to tolerogenic processes by activating metabolic pathways responsive to amino acid withdrawal and aryl hydrocarbon signaling, respectively. Sustained IDO elevation creates local immune privilege that protects tissues from immune-mediated damage and allows tissues to heal. This response occurs in lymphoid tissues when DNA released by dying tissue cells is sensed to induce specialized DC subsets to acquire tolerogenic phenotypes. The tolerogenic effects of IDO also promote tumorigenesis and help establish immune checkpoints in cancer, as malignant cells are protected from immune surveillance. Similar processes may attenuate host immunity to some pathogens that persist in immunocompetent individuals. However, if inflammation with IDO involvement is not resolved, chronic immune activation at such sites causes progressive tissue damage over time. Another effect of sustained IDO activity is enhanced pain sensitivity, as some Trp catabolites produced by cells expressing IDO are neuroactive. In this review, we summarize links between IDO and chronic inflammatory diseases and discuss prospects for exploiting IDO and Trp catabolism to suppress immunity and promote tolerance for clinical benefit, with particular emphasis on protecting tissues from destructive autoimmunity.