Alterations of aryl hydrocarbon receptor signaling in autoimmune hepatitis

自身免疫性肝炎中芳烃受体信号传导的改变

• 批准号: 10117722
• 负责人: Maria Serena Longhi
• 金额: $ 38.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117722
• 关键词: ARNT gene; Acute Hepatitis; Adenosine; Apyrase; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Bilirubin; Biliverdine; Binding; CD4 Positive T Lymphocytes; Catabolism; Cells; Chronic; Clinical; Complex; Concanavalin A; Data; Development; Dietary Component; Disease; Disease Progression; Disease remission; Down-Regulation; Effector Cell; Environmental Pollutants; Environmental Risk Factor; Equilibrium; Estrogen Receptor alpha; Etiology; Exposure to; Functional disorder; Generations; Genetic Transcription; Goals; Heme; Homeostasis; Human; Icterus; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Immunotherapeutic agent; Impairment; Inflammation; Inflammatory; Intervention; Investigation; Kynurenine; Life; Ligands; Link; Liver; Liver diseases; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Mus; NF-kappa B; Organ; Pathogenicity; Patients; Pattern; Pharmacology; Predisposition; Property; Quercetin; Receptor Activation; Receptor Signaling; Refractory; Regimen; Regulation; Regulatory T-Lymphocyte; Relapse; Resistance; Signal Transduction; Small Interfering RNA; T cell response; Testing; Time; Tissues; Toxin; Transforming Growth Factor beta; Transplantation; Trichostatin A; Tryptophan; Tumor Suppressor Proteins; Up-Regulation; Xenobiotics; acute liver injury; adaptive immunity; aryl hydrocarbon receptor ligand; chetomin; chronic liver disease; chronic liver injury; extracellular; hypoxia inducible factor 1; immune activation; immunoregulation; in vivo Model; inhibitor/antagonist; innovation; insight; liver biopsy; metabolic profile; mouse model; new therapeutic target; peripheral blood; receptor binding; receptor function; reconstitution; response; side effect

Abstract Autoimmune hepatitis (AIH) is a severe liver disease of unknown etiology that typically follows a relapsing- remitting course and may often become refractory to conventional immunosuppression. This important illness may progress over months or years to end-stage liver disease with jaundice, requiring transplantation in about 20% of cases. Dysfunctional Tregs co-exist, in AIH, along with heightened Th17 immune responses, which are refractory to immunoregulation. CD39 is an ectonucleotidase that hydrolyzes extracellular ATP to ultimately generate immunosuppressive adenosine. This ectoenzyme is expressed by Tregs and a subset of effector Th17 cells, where it marks the acquisition of regulatory properties. Induction of CD39 results, at least in part, from activation of aryl hydrocarbon receptor (AhR), which mediates toxin responses to modulate Treg and Th17 cell immunity. AhR binds exogenous and endogenous ligands, including xenobiotics and heme derivatives e.g. unconjugated bilirubin. AhR functions are mediated through interactions with the aryl hydrocarbon receptor nuclear translocator or other ‘non-canonical’ binding factors like the estrogen receptor-a (Era) or the Kruppel- like factor 6. AhR is also regulated by hypoxia inducible factor 1 alpha (HIF-1a), the AhR repressor (AhRR) and TGF-b and is induced by NF-kB through the Rel-A subunit. We have noted that AIH-derived Tregs and Th17 cells express decreased levels of CD39. This alteration is associated with defective Treg function and persistence of pro-inflammatory Th17 cells. We also observe that both Tregs and Th17 cells fail to upregulate CD39 in response to AhR activation. Tregs and Th17 cells in AIH also express heightened Era, KLF6, AhRR and HIF-1a levels. These data suggest that AhR binding to non-canonical partners and/or aberrant AhR regulation might interfere with T cell responses, ultimately resulting in CD39 downregulation in AIH. We therefore hypothesize that Treg and Th17 cell purinergic dysfunction in AIH can be linked to aberrant AhR signaling and/or regulation. These alterations perpetuate Treg/Th17 cell imbalances that favor tissue damage and disease progression in AIH. In Aim 1, we will determine whether aberrant AhR interactions with non-canonical partners impact the purinergic response, metabolic profiles and function of Tregs and Th17 cells; either derived from the peripheral blood or liver biopsies of AIH patients. In Aim 2, we will define the cellular mechanisms regulating AhR signaling and how these impact CD39 in AIH-derived Tregs and Th17 cells. In both Aims 1 and 2, the effects of altered AhR signaling and regulation will be also tested in an in vivo model of acute hepatitis induced by Concanavalin-A in immunodeficient NOD/scid/gamma mice. Lastly, in Aim 3, we will test innovative strategies a) to enhance AhR signaling, either by pharmacological blockade of HIF-1a or AhRR; and/or b) directly boost CD39 activity through administration of exogenous ADPase. Our investigations will provide mechanistic insights into autoimmune tissue damage in AIH and, notably, will aid identifying novel therapeutic targets to control inflammation and halt disease progression in AIH and other chronic liver illnesses.

摘要 自身免疫性肝炎（AIH）是一种病因不明的严重肝病，通常在复发后出现， 缓解过程，并可能经常成为传统的免疫抑制难治性。这个重要的疾病 可能会在数月或数年内进展为伴有黄疸的终末期肝病， 20%的案件。在AIH中，功能失调的Th 17与Th 17免疫应答的增强沿着， 免疫调节难治的。CD 39是一种外核苷酸酶，其水解细胞外ATP，最终 产生免疫抑制腺苷。这种胞外酶由Tcl 4和效应子Th 17的一个亚群表达 细胞，在那里它标志着收购的监管性质。CD 39的诱导至少部分来自于 激活芳香烃受体（AhR），其介导毒素应答以调节Treg和Th 17细胞 免疫力AhR结合外源性和内源性配体，包括外源性物质和血红素衍生物，例如 未结合胆红素AhR功能通过与芳烃受体的相互作用介导 核转运蛋白或其他“非经典”结合因子，如雌激素受体-a（Era）或Kruppel- 比如因子6。AhR还受缺氧诱导因子1 α（HIF-1a）、AhR阻遏物（AhRR）和 NF-kB通过Rel-A亚基诱导TGF-β表达。我们已经注意到，AIH衍生的T细胞和Th 17 细胞表达降低水平的CD 39。这种改变与Treg功能缺陷有关， 促炎性Th 17细胞的持续存在。我们还观察到，Tcl 4和Th 17细胞都不能上调 CD 39对AhR活化的响应。AIH患者的Th和Th 17细胞也表达Era、KLF 6、AhRR HIF-1a水平。这些数据表明，AhR与非典型伴侣和/或异常AhR的结合可能是一个重要因素。 调节可能干扰T细胞应答，最终导致AIH中CD 39下调。因此我们 假设AIH中Treg和Th 17细胞嘌呤能功能障碍可能与异常AhR信号传导有关 和/或监管。这些改变使Treg/Th 17细胞失衡永久化，有利于组织损伤和疾病 AIH的进展。在目标1中，我们将确定是否异常AhR与非典型合作伙伴的相互作用 影响嘌呤能反应、代谢谱和TcR和Th 17细胞的功能;无论是来自 AIH患者的外周血或肝活检。在目标2中，我们将定义调节 AhR信号传导以及这些信号传导如何影响AIH衍生的TcR和Th 17细胞中的CD 39。在目标1和2中， 改变的AhR信号传导和调节也将在体内急性肝炎模型中进行测试， 免疫缺陷NOD/scid/gamma小鼠中的伴刀豆球蛋白A。最后，在目标3中，我们将测试创新战略 a）通过药理学阻断HIF-1 a或AhRR来增强AhR信号传导;和/或B）直接加强 通过施用外源性ADVANE的CD 39活性。我们的调查将提供机械的见解 研究AIH的自身免疫组织损伤，特别是将有助于确定新的治疗靶点， 在AIH和其他慢性肝病中，炎症和阻止疾病进展。