The Role of the Adenosine Receptor in Th Cell Development and Function

腺苷受体在 Th 细胞发育和功能中的作用

• 批准号: 10307144
• 负责人: Peter B. Ernst
• 金额: $ 50.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307144
• 关键词: ADORA2A gene; Address; Adenosine; Affect; American; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antiinflammatory Effect; Bacteria; Bacteroides fragilis; Binding; Biology; Catabolism; Cells; Cicatrix; Colitis; Communities; Crohn' s disease; Data; Dendritic Cells; Development; Diagnostic tests; Disease; Disease susceptibility; Energy Metabolism; Environment; Enzymes; Equilibrium; Eragrostis; Frequencies; Funding; Gastrointestinal tract structure; Genes; Genomic approach; Glycolysis; Goals; Homeostasis; Human; Immune; Immune response; Immunobiology; Immunologics; Immunology; Immunotherapy; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knockout Mice; Knowledge; Lymphocyte; Lymphoid; Lymphoid Cell; Maintenance; Mediating; Messenger RNA; Metabolic; Metabolism; Microbe; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Organism; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Phenotype; Polysaccharides; Predisposition; Prevention; Production; Property; Purinergic P1 Receptors; Purines; Rag1 Mouse; Regulatory T-Lymphocyte; Role; Series; Shapes; Signal Transduction; Source; Testing; Therapeutic; Ulcerative Colitis; adenylate kinase; antimicrobial; chronic infection; cytokine; dysbiosis; experimental study; flexibility; functional genomics; gastrointestinal; glucose uptake; gut microbiota; immunoregulation; insight; microbial; microbial community; microbiome; microbiota; novel; pathobiont; purine metabolism; response; therapeutic development

ABSTRACT/SUMMARY Immunological homeostasis reflects a balance between the host response and the antigenic environment. In mucosal immunology, inflammatory bowel diseases (IBD), including ulcerative colitis or Crohn’s disease, reflect a disruption in homeostasis with exaggerated host responses to the local microbiota in genetically susceptible hosts. Our microbial communities are dynamic so regulatory Th cells induced in the periphery (pTreg) are important to maintain a flexible homeostasis with these diverse organisms. Many factors modify the metabolic balance that maintains homeostasis and Treg function. Relevant to this proposal, studies have associated a disruption in adenosine metabolism with IBD in humans and in animal models. Adenosine is a purine metabolite derived from ATP through its conversion to ADP and 5’AMP by CD39 while CD73 continues the metabolism to adenosine. As the production of ATP from dead cells or bacteria is pro-inflammatory, its catabolism to adenosine is one means to restrict inflammation. Adenosine has direct anti-inflammatory properties mediated primarily through the A2A adenosine receptor (A2AAR) expressed by lymphocytes as well as antigen presenting cells and innate lymphoid cells. Moreover, we present new findings suggesting that adenosine shifts the energy metabolism in Th cells in order to confer its anti-inflammatory effects. Other data show that the absence of adenosine initiates the expansion of pathogenic Th cells, a decrease in Treg, and selects for microbiota that transmit susceptibility to colitis. The hypothesis for this study is that adenosine is required to maintain immunological homeostasis in the digestive tract. More specifically, disrupting adenosine production or responsiveness impacts lymphoid cell fate that subsequently changes bacterial colonization, creates a dysbiosis and promotes inflammation. The broad objective of the project is to define the role of purine metabolism on the control of immunological homeostasis in the gut as addressed in the following interrelated Specific Aims: Aim 1: Identify how lymphoid-microbial homeostasis relies on adenosine. Aim 2: Determine how adenosine controls protective responses to microbiota Aim 3: Define the role of purine metabolism in controlling lymphoid cell fate. . The proposed experiments will explore novel aspects of immunological homeostasis. These studies will have a positive impact on the basic understanding of lymphoid cell plasticity and provide new knowledge that can be used to expedite the identification and development of therapeutic strategies for immune-mediated diseases.

摘要/总结 免疫稳态反映了宿主反应和抗原环境之间的平衡。 在粘膜免疫学中，炎症性肠病（IBD），包括溃疡性结肠炎或克罗恩病， 这反映了体内平衡的破坏，宿主对遗传学上的局部微生物群的反应过度。 易感宿主我们的微生物群落是动态的，因此在外周诱导调节性Th细胞 （pTreg）对于维持这些不同生物体的灵活稳态是重要的。许多因素改变了 维持体内平衡和Treg功能的代谢平衡。与这项建议有关的研究有： 在人类和动物模型中，腺苷代谢的破坏与IBD相关。腺苷是一种 由ATP通过CD 39转化为ADP和5 'AMP而衍生的嘌呤代谢物，而CD 73继续 代谢为腺苷。由于死亡细胞或细菌产生的ATP是促炎性的， 腺苷的催化剂是抑制炎症的一种手段。腺苷具有直接抗炎作用 主要通过淋巴细胞表达的A2 A腺苷受体（A2 AAR）介导的性质 如抗原呈递细胞和先天淋巴细胞。此外，我们提出的新发现表明， 腺苷改变Th细胞中的能量代谢以赋予其抗炎作用。其他数据 表明腺苷的缺乏启动了致病性Th细胞的扩增，Treg的减少，以及 选择传播结肠炎易感性的微生物群。这项研究的假设是，腺苷是 维持消化道内的免疫稳态所需。更具体地说， 产生或反应性影响淋巴细胞的命运，随后改变细菌定植， 造成生态失调并促进炎症。该项目的总体目标是确定 嘌呤代谢对肠道免疫稳态控制的影响，如下所述 相互关联的具体目标： 目的1：确定淋巴-微生物平衡如何依赖腺苷。 目的2：确定腺苷如何控制对微生物群的保护性反应 目的3：明确嘌呤代谢在控制淋巴细胞命运中的作用。. 拟议的实验将探索免疫稳态的新方面。这些研究将 对淋巴细胞可塑性的基本认识产生积极影响，并提供新的知识， 可用于加速免疫介导的肿瘤的治疗策略的鉴定和开发， 疾病

项目成果

The A2B adenosine receptor promotes Th17 differentiation via stimulation of dendritic cell IL-6.

A2b腺苷受体通过刺激树突状细胞IL-6促进Th17分化。

• DOI: 10.4049/jimmunol.1100117
• 发表时间: 2011-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wilson JM;Kurtz CC;Black SG;Ross WG;Alam MS;Linden J;Ernst PB
• 通讯作者: Ernst PB

Elevated levels of intestinal inflammation in Clostridium difficile infection associated with fluoroquinolone-resistant C. difficile.

与氟喹诺酮耐药艰难梭菌相关的艰难梭菌感染肠道炎症水平升高。

• DOI: 10.1016/j.jhin.2009.05.013
• 发表时间: 2009
• 期刊: The Journal of hospital infection
• 作者: Pawlowski,SW;Archbald-Pannone,L;Carman,RJ;Alcantara-Warren,C;Lyerly,D;Genheimer,CW;Gerding,DN;Guerrant,RL
• 通讯作者: Guerrant,RL

Immunological alterations mediated by adenosine during host-microbial interactions.

• DOI: 10.1007/s12026-011-8207-0
• 发表时间: 2011-05
• 期刊: IMMUNOLOGIC RESEARCH
• 影响因子: 4.4
• 作者: Drygiannakis, Ioannis;Ernst, Peter B.;Lowe, David;Glomski, Ian J.
• 通讯作者: Glomski, Ian J.

Validated gene expression biomarker analysis for biopsy-based clinical trials in ulcerative colitis.

经验证的基因表达生物标志物分析用于溃疡性结肠炎基于活检的临床试验。

• DOI: 10.1111/apt.12862
• 发表时间: 2014
• 期刊: Alimentary pharmacology & therapeutics
• 影响因子: 7.6
• 作者: Boland,BS;Boyle,DL;Sandborn,WJ;Firestein,GS;Levesque,BG;Hillman,J;Zhang,B;Proudfoot,J;Eckmann,L;Ernst,PB;Rivera-Nieves,J;Pola,S;Copur-Dahi,N;Chang,JT
• 通讯作者: Chang,JT

Microbial-Driven Immunological Memory and Its Potential Role in Microbiome Editing for the Prevention of Colorectal Cancer.

• DOI: 10.3389/fcimb.2021.752304
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Campillo-Gimenez L;Rios-Covian D;Rivera-Nieves J;Kiyono H;Chu H;Ernst PB
• 通讯作者: Ernst PB