Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression
Activation of the Aryl Hydrocarbon Receptor Ameliorates Acute Rejection of Rat Liver Transplantation by Regulating Treg Proliferation and PD-1 Expression
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DOI：
10.1097/tp.0000000000004205
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发表时间：
2022-11-01
期刊：
影响因子：
6.2
通讯作者：
Xu, Junming
中科院分区：
文献类型：
--
作者：
Cao, Wanyue;Lu, Jing;Xu, Junming
背景芳烃受体（Aryl Hydrocarbon Receptor，AhR）在免疫调节中起重要作用。然而，AhR在大鼠肝移植（LT）中的作用尚未被探索。方法.评价了N-（3，4-二甲氧基肉桂酰基）邻氨基苯甲酸（3，4-DAA）和2-甲基-2H-吡唑-3-羧酸酰胺（CH 223191）的安全性和不良反应。我们使用最佳剂量的两种药物，3，4-DAA，用于介导AhR激活的药物，和CH 223191，AhR的拮抗剂（3，4-DAA，CH 223191，和3，4-DAA + CH 223191），每天腹腔内给予受体，以研究AhR在大鼠LT模型中的作用。采用Western blot、实时荧光定量PCR、免疫荧光等方法观察移植肝组织病理学变化、细胞浸润情况、AhR和PD-1的变化。流式细胞术检测受体脾和外周血单个核细胞中Foxp 3（+）和PD-1（+）T细胞的含量。体外分离CD 4（+）T细胞后，用不同AhR配体处理，观察其分化方向和PD-1表达水平。结果3，4-DAA激活AhR延长了存活时间并改善了移植物排斥反应，这与肝脏中AhR和PD-1的表达增加以及受体脾脏、肝脏和外周血单核细胞中Foxp 3（+）T细胞和PD-1（+）T细胞的增加有关。在体外，用3，4-DAA孵育的原代T细胞介导Treg和PD-1（+）T细胞比例的增加。然而，用CH 223191抑制AhR在LT模型和体外均逆转了这些作用。结论.结果提示，AhR激活可能通过增加Treg的比例和PD-1的表达来减少大鼠急性排斥反应的发生。
Background. Aryl hydrocarbon receptor (AhR) plays important roles in modulating immune responses. However, the role of AhR in rat liver transplantation (LT) has not been explored. Methods. Safety and side effects of N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) and 2-methyl-2H-pyrazole-3-carboxylic acid amide (CH223191) were evaluated. We used optimal doses of 2 drugs, 3,4-DAA, a drug used for mediating AhR activation, and CH223191, antagonist of AhR (3,4-DAA, CH223191, and 3,4-DAA + CH223191), intraperitoneally administered to recipients daily to investigate the role of AhR in the rat LT model. The recipient livers were used to observe the pathological changes, the cells infiltrating the graft, and changes of AhR and programmed death-1 (PD-1) by Western blot, real-time polymerase chain reaction, and immunofluorescence assays. The contents of Foxp3(+) and PD-1(+) T cells in the recipient spleen and peripheral blood mononuclear cells were evaluated by flow cytometry. In vitro, after isolating CD4(+) T cells, they were treated with different AhR ligands to observe the differentiation direction and PD-1 expression level. Results. The activation of AhR by 3,4-DAA prolonged survival time and ameliorated graft rejection, which were associated with increased expression of AhR and PD-1 in the livers and increased Foxp3(+) T cells and PD-1(+) T cells in recipient spleens, livers, and peripheral blood mononuclear cells. In vitro, primary T cells incubated with 3,4-DAA mediated increased proportion of Treg and PD-1(+) T cells. However, the suppression of AhR with CH223191 reverses these effects, both in the LT model and in vitro. Conclusions. Our results indicated that AhR activation might reduce the occurrence of rat acute rejection by increasing the proportion of Treg and the expression of PD-1.