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Immunomodulatory effects of bilirubin are mediated through aryl hydrocarbon receptor, O2 and purinergic pathways

胆红素的免疫调节作用是通过芳烃受体、O2 和嘌呤能途径介导的

基本信息

批准号：
10090589
负责人：
Maria Serena Longhi
金额：
$ 38.97万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090589
关键词：
ABCB1 gene ARNT gene ARNT protein ATP-Binding Cassette Transporters Adenosine Adoptive Transfer Antioxidants Apyrase Aryl Hydrocarbon Receptor Bile Pigments Bilirubin Biliverdine CYP1A1 gene Catabolism Cells Cessation of life Chronic Chronic Disease Clinical Course of Disease Colitis Cytochromes Data Defect Development Dimerization Disease Disease Progression Effector Cell Equilibrium Experimental Models Exposure to FOXP3 gene Failure Gene Deletion Generations Genetic Predisposition to Disease Gilbert Disease Glucuronosyltransferase Goals Heme Heterodimerization Human Hypoxia Icterus Immune Immune Response Genes Immune System Diseases Immune response Immune system Immunosuppression Impairment In Vitro Indinavir Individual Inflammation Inflammatory Inflammatory Bowel Diseases Intervention Ligation Link Lipids Liver diseases Mediating Mediator of activation protein Morbidity - disease rate Multienzyme Complexes Mus Mutation Nucleosides Nucleotides Oxygen Pathway interactions Patients Property Proteins Pump Receptor Signaling Refractory Regimen Regulatory T-Lymphocyte Risk Ritonavir Role Secondary to Signal Transduction Spontaneous Remission Stress System T-Lymphocyte Testing Therapeutic Toxic effect Toxin Transgenic Mice Up-Regulation Xenobiotics aryl hydrocarbon receptor ligand cancer risk combinatorial disease phenotype effector T cell experimental study extracellular gut bacteria gut microbiota heme oxygenase-1 hypoxia inducible factor 1 immune activation immunoregulation in vivo inflammatory disease of the intestine innovation islet allograft mouse model novel strategies novel therapeutics prevent receptor response

项目摘要

Abstract Inflammatory bowel disease (IBD) may develop as a consequence of imbalanced immune system responses to altered gut microbiota, in genetically predisposed individuals, some of whom have defined mutations in immune response genes. New approaches are important, as IBD is a serious and common illness, which often becomes refractory to conventional immunosuppression. Chronic illness is associated with substantial morbidity, cancer risk and early death. Curiously, jaundiced patients may have spontaneous remissions from immunologic diseases, including IBD. Also, people with Gilbert's disease are less likely to develop IBD and bile pigments have been shown to induce tolerance to islet allografts and ameliorate experimental colitis. Biliverdin- bilirubin, end products of heme catabolism by heme oxygenase-1 (HO-1) have substantive immunomodulatory effects linked to the boosting of regulatory FoxP3+ T-cells (Tregs) in vitro. These effects may be impacted by expression of the multidrug resistance protein 1 (MDR1); an ATP-binding cassette transporter that pumps xenobiotics and host endogenous mediators, e.g. unconjugated bilirubin (UCB), out of cells. Bilirubin is known to interact with the aryl hydrocarbon receptor (AhR), a receptor more typically involved in responses to xenobiotics and toxins. Both the AhR and the hypoxia-inducible-factor-1-alpha (HIF-1α) closely modulate expression of CD39, an ectonucleotidase expressed by the vasculature and immune cells and critically responsible for generation of immune suppressive adenosine. We provide preliminary evidence that expression of AhR is impaired in Th17 cells from IBD patients. These Th17 cells are also defective at upregulating CD39 upon exposure of UCB in vitro. We also note that Th17 cells from IBD patients, substantively upregulate HIF-1α, which in turn further competitively inhibits AhR- mediated boosts to CD39.We propose that lipid soluble UCB induces tolerance via Treg and `suppressor' Th17 cells in IBD, through engagement of pathways involving AhR/HIF-1α and with purinergic signaling being the effector pathway. Our aims study the impact of UCB upon the Treg-Th17 cell immune axis, as modulated by the AhR, HIF-1α and the CD39-dependent pathways in murine models of experimental colitis. We dissect out how UCB impacts colitic disease phenotype and immune responses. Finally we will determine whether interventions aimed to boost UCB either by interfering with HIF-1α, boosting CD39 ectonucleotidase activity (e.g. apyrase), inhibiting bilirubin conjugation by UDP-glucuronosyltransferase (e.g. indinavir), or modulating MDR1 expression (e.g. ritonavir) can provide beneficial effects with limited toxicity. These approaches will be tested in experimental colitis in vivo and in vitro experimental systems using cells from IBD patients. In addition to providing unique connections between bilirubin, other environmental signals, O2-mediated stress and purinergic signaling, our studies will contribute to a better understanding of IBD and will also illuminate potential therapeutic approaches to curb inflammation and halt disease progression.

摘要炎症性肠病（IBD）可能是免疫系统反应失衡的结果改变肠道微生物群，在遗传易感个体中，其中一些人已经定义了免疫反应基因新方法很重要，因为IBD是一种严重而常见的疾病，变得对传统的免疫抑制很难治疗。慢性病与大量的发病率、癌症风险和过早死亡。奇怪的是，黄疸患者可能有自发缓解，免疫性疾病，包括IBD。此外，患有吉尔伯特病的人不太可能发展为IBD和胆汁色素已显示诱导对胰岛同种异体移植物的耐受性并改善实验性结肠炎。胆绿素- 胆红素是血红素加氧酶-1（HO-1）催化血红素生成的终产物，具有显著的免疫调节作用，与体外调节性FoxP 3 + T细胞（T细胞）的加强有关的作用。这些影响可能受到多药耐药蛋白1（MDR 1）的表达;一种ATP结合盒转运蛋白，外源性物质和宿主内源性介质，例如未结合胆红素（UCB），从细胞中排出。已知胆红素与芳烃受体（AhR）相互作用，芳烃受体是一种更典型地参与代谢的受体。对外源性物质和毒素的反应。AhR和缺氧诱导因子-1 α（HIF-1α）与细胞凋亡密切相关。调节CD 39的表达，CD 39是一种由脉管系统和免疫细胞表达的外核苷酸酶，对免疫抑制腺苷的产生起关键作用。我们提供的初步证据表明，AhR的表达受损的Th 17细胞从IBD患者。这些在体外暴露于UCB时，Th 17细胞在上调CD 39方面也有缺陷。我们还注意到，Th 17 来自IBD患者的细胞实质上上调HIF-1α，这反过来又进一步竞争性抑制AhR-1 α。我们认为脂溶性UCB通过Treg和“抑制性”Th 17诱导耐受 IBD中的细胞，通过参与涉及AhR/HIF-1α的途径，并与嘌呤能信号转导有关。效应子途径我们的目的是研究UCB对Treg-Th 17细胞免疫轴的影响，如通过调节实验性结肠炎小鼠模型中AhR、HIF-1α和CD 39依赖性通路。我们解剖出 UCB如何影响结肠炎疾病表型和免疫应答。最后，我们将确定干预措施旨在通过干扰HIF-1α、增强CD 39外核苷酸酶活性来增强UCB (e.g.腺苷三磷酸双磷酸酶）、通过UDP-葡萄糖醛酸基转移酶抑制胆红素缀合（例如茚地那韦）或调节 MDR 1表达（例如利托那韦）可以提供有益的效果和有限的毒性。这些方法将使用来自IBD患者的细胞在体内和体外实验系统中在实验性结肠炎中进行测试。此外提供胆红素，其他环境信号，O2介导的压力和嘌呤能信号，我们的研究将有助于更好地了解IBD，也将阐明潜在的治疗方法来抑制炎症和阻止疾病进展。

项目成果

期刊论文数量（40）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models.

DOI：
10.1172/jci157431
发表时间：
2022-07-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Zhang, Haohai;Feng, Lili;Mello, Paola de Andrade;Mao, Changchuin;Near, Richard;Csizmadia, Eva;Chan, Leo Li-Ying;Enjyoji, Keiichi;Gao, Wenda;Zhao, Haitao;Robson, Simon C.
通讯作者：
Robson, Simon C.

Lactobacillus reuteri joins the liver autoimmune arena.

Reuteri乳杆菌加入了肝自动免疫竞技场。