Mutual antagonism between indoleamine 2,3-dioxygenase 1 and nuclear factor E2-related factor 2 regulates the maturation status of DCs in liver fibrosis
Mutual antagonism between indoleamine 2,3-dioxygenase 1 and nuclear factor E2-related factor 2 regulates the maturation status of DCs in liver fibrosis
复制标题
吲哚胺2,3-双加氧酶1与核因子E2相关因子2的相互拮抗作用调节肝纤维化中DC的成熟状态
DOI：
10.1016/j.freeradbiomed.2020.07.038
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发表时间：
2020-11-20
影响因子：
7.4
通讯作者：
Lv, Zhiping
中科院分区：
文献类型：
--
作者：
Mo, Chan;Xie, Shuwen;Lv, Zhiping
由于分子发病机制的少见，肝纤维化可发展为肝硬变和肝细胞癌，目前尚无有效的治疗方法。吲哚胺2，3-双加氧酶1(IDO1)可在抗原提呈细胞(APC)上检测到，并调节各种免疫反应。然而，IDO1在肝纤维化过程中对树突状细胞(DC)的调节作用鲜有报道。在此，我们发现，在CCl4诱导的肝纤维化过程中，肝脏IDO1表达上调，同时CD11c(+)CD80(+)、CD11c(+)CD86(+)、CD11c(+)CD40(+)和CD11c(+)MHCII(+)细胞频率显著下降，随后T细胞增殖率下降，而IDO1(-/-)小鼠的这些变化明显逆转。腺相关病毒载体血清9型(AAV9)过表达IDO1显著抑制DC的成熟状态，加重纤维化。体外研究表明，IDO1(-/-)小鼠BMDCs的CD80、CD86、CD40和MHCII表达显著升高。此外，经IDO1抑制剂(1-甲基D-色氨酸)刺激后，WT小鼠BMDCs的成熟度显著增加。核因子E2相关因子2(Nrf2)是细胞对氧化损伤和炎症的适应性反应的关键调节因子，在WT纤维化小鼠的肝脏中表现出显著的减少，然而，IDO1基因敲除增加了Nrf2的蛋白水平。此外，IDO1和Nrf2的表达呈现反向共定位模式，表明异位表达的IDO1下调了Nrf2的表达。此外，在Nrf2(-/-)纤维化小鼠的肝脏中也观察到IDO1的上调。综上所述，这些数据揭示了IDO1和NRF2在肝纤维化过程中对DC的迁移状态的相互拮抗作用。
Liver fibrosis can develop into liver cirrhosis and hepatocellular carcinoma substantially without effective available treatment currently due to rarely characterized molecular pathogenesis.Indoleamine 2,3-dioxygenase 1(IDO1) can be detected on antigen-presenting cells (APCs) and modulates various immune responses. However, the role of IDO1 in the regulation of dendritic cells (DCs) during liver fibrosis is rarely reported. Here, we found that hepatic IDO1 was up-regulated during CCL4-induced liver fibrosis, which accompanied by a significant decrease in the frequencies of CD11c(+)CD80(+), CD11c(+)CD86(+), CD11c(+)CD40(+) and CD11c(+)MHCII(+) cells and a reduction in the subsequent T cell proliferation rate, whereas these changes were reversed significantly in IDO1(-/-) mice. Overexpressing IDO1 by adeno-associated viral vector serotype 9 (AAV9) significantly inhibited the maturation status of DCs, worsened fibrosis. In vitro studies showed that significantly elevated CD80, CD86, CD40 and MHCII expression were observed in BMDCs derived from IDO1(-/-) mice. Moreover, the maturation of BMDCs derived from WT mice were significantly increased after stimulated with IDO1 inhibitor (1-methylD -tryptophan). Nuclear factor E2-related factor 2 (Nrf2), a key regulator of the cellular adaptive response to oxidative insults and inflammation, exhibited a markedly decrease in the liver of WT fibrotic mice, nevertheless, knockout of IDO1 enhanced the protein level of Nrf2. Moreover, the expression of IDO1 and Nrf2 exhibited inverse colocalization pattern suggesting that ectopically expressed IDO1 down-regulated Nrf2. Additionally, up-regulation of IDO1 was also observed in the livers of Nrf2(-/-) fibrotic mice. Taken together, these data uncovered mutual antagonism between IDO1 and Nrf2 on the ma turation status of DCs during hepatic fibrosis.