Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis.
Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis.
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DOI：
10.1016/j.jhep.2020.06.044
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发表时间：
2021-01
影响因子：
25.7
通讯作者：
Longhi MS
中科院分区：
文献类型：
--
作者：
Vuerich M;Harshe R;Frank LA;Mukherjee S;Gromova B;Csizmadia E;Nasser IAM;Ma Y;Bonder A;Patwardhan V;Robson SC;Longhi MS
在自身免疫性肝炎（AIH）中，Treg和Th 17细胞之间的不平衡与低水平的CD 39有关，CD 39是一种水解ATP的胞外酶，最终产生免疫抑制性腺苷。CD 39的上调由芳香烃受体（AHR）的活化引起，芳香烃受体介导毒素应答以调节T细胞免疫。在与外源性或内源性配体结合后，AHR与芳香烃受体核转运子（ARNT）或其他“非经典”结合因子如雌激素受体α（Erα）二聚化以调节基因转录。AHR/ARNT复合物又受缺氧诱导因子-1 α（HIF-1α）和芳香烃受体阻遏物（AHRR）的调节。在这项研究中，我们研究了AHR信号的改变是否是AIH Treg和Th 17细胞中CD 39表达和功能缺陷的基础，从而导致调节/效应细胞失衡。从49名AIH患者和21名健康受试者（HS）的外周血中获得Treg和Th 17细胞，检测其对AHR内源性和外源性配体的反应。当与HS相比时，AIH Treg和Th 17-细胞显示出对AHR活化的受损应答，如通过受损的CD 39上调、延迟的胞外酶活性增加和缺陷的Treg抑制功能所反映的。这些损伤至少部分是由于Treg中AHRR和Erα水平升高以及Th 17-细胞中HIF-1α水平升高所致，并在分子阻断后恢复。重要的是，在AIH Treg中，AHR对Erα的结合亲和力高于ARNT。在AIH中，高水平的AHRR和HIF-1α抑制Treg和Th 17-细胞中的AHR信号传导。AHR与Erα的非典型结合进一步放大了有效CD 39上调的缺乏。阻断这些抑制性和/或非经典活化途径代表了恢复AIH中CD 39和免疫稳态的潜在治疗方法。在自身免疫性肝炎患者中，Treg和Th 17效应淋巴细胞之间的失衡与芳香烃受体途径的功能障碍有关，这是由异常抑制或非典型激活引起的。这些改变导致Treg和Th 17细胞上调CD 39（免疫调节的关键胞外酶）的能力受损，并且导致Treg抑制能力缺陷。阻断过度的芳烃受体抑制或非经典激活可能代表了一种新的治疗策略，以控制炎症，同时恢复Treg/Th 17免疫平衡的自身免疫性肝炎。
In autoimmune hepatitis (AIH) imbalance between Treg and Th17-cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl-hydrocarbon-receptor (AHR), which mediates toxin responses to modulate T-cell immunity. Upon binding to exogenous or endogenous ligands, AHR dimerizes with the aryl-hydrocarbon-receptor-nuclear-translocator (ARNT) or other ‘non-canonical’ binding factors like oestrogen-receptor-α (Erα) to modulate gene transcription. The AHR/ARNT complex is in turn regulated by hypoxia-inducible-factor-1α (HIF-1α) and the aryl-hydrocarbon receptor-repressor (AHRR). In this study we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Treg and Th17-cells, therefore contributing to regulatory/effector cell imbalance. Treg and Th17-cells, obtained from the peripheral blood of 49 AIH patients and 21 healthy subjects (HS), were tested for response to AHR endogenous and exogenous ligands. When compared to HS, AIH Treg and Th17-cells displayed impaired response to AHR activation, as reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Treg and high HIF-1α in Th17-cells and were reverted upon molecular blockade. Importantly, in AIH Treg, the binding affinity of AHR was higher for Erα than ARNT. In AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Treg and Th17-cells. AHR non-canonical binding to Erα further amplifies lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH. In patients with autoimmune hepatitis imbalance between Treg and Th17 effector lymphocytes is linked to dysfunction of aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations lead to impaired Treg and Th17-cell ability to upregulate CD39, an ectoenzyme key to immunoregulation, and in defective Treg ability to suppress. Blockade of excessive aryl hydrocarbon receptor inhibition or non-canonical activation might represent a novel therapeutic strategy to control inflammation while restoring Treg/Th17 immune balance in autoimmune hepatitis.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
13.5
作者：
Liaskou, Evaggelia;Karikoski, Marika;Reynolds, Gary M.;Lalor, Patricia F.;Weston, Chris J.;Pullen, Nick;Salmi, Marko;Jalkanen, Sirpa;Adams, David H.
通讯作者：
Adams, David H.
影响因子：
4.6
作者：
Ambade A;Satishchandran A;Szabo G
通讯作者：
Szabo G
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64.5
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Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
影响因子：
8.7
作者：
Allard B;Longhi MS;Robson SC;Stagg J
通讯作者：
Stagg J