Role of TRIF-Dependent TLR Signaling in Intestinal Mucosa

TRIF 依赖性 TLR 信号转导在肠粘膜中的作用

• 批准号: 10225616
• 负责人: Stephan R. Targan
• 金额: $ 43.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225616
• 关键词: Address; Affect; Animal Model; Award; Bacteria; Biological Assay; Cell Survival; Cells; Chronic; Colitis; Complex; Crohn' s disease; Data; Data Analyses; Future; Generations; Genes; Genetic Transcription; Genetic study; Helper-Inducer T-Lymphocyte; IFNAR1 gene; IL17 gene; Ileitis; Immunologic Memory; Immunology; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interferon-beta; Interferons; Interleukin-10; Intestinal Mucosa; Intestines; Lead; Link; Maintenance; Mediating; Mediation; Memory; Modeling; Molecular; Mucous Membrane; Mus; Mutation; Natural Immunity; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Play; Population; Predisposition; Rag1 Mouse; Recurrent disease; Regulation; Relapse; Risk; Role; STAT1 gene; STAT3 gene; Severities; Signal Transduction; Susceptibility Gene; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Variant; Virus; adaptive immunity; cell type; chronic inflammatory disease; commensal bacteria; cytokine; flexibility; genetic variant; genome wide association study; in vivo; inflammatory disease of the intestine; insight; intestinal homeostasis; mouse model; novel; novel strategies; peripheral blood; precision medicine; response

Extensive studies have shown that an aggressive mucosal T cell subset that reacts to intestinal bacteria plays an important role in the cause of inflammatory bowel disease (IBD). These aggressive T cells are thought to live long as immune-memory cells in peripheral blood and contribute to the chronicity and the relapse of the disease. Evidence further suggests that a type of T cells, which flexibly secretes different effector molecules, contributes to the complex pathogenesis of IBD. Another T cell subset, T follicular helper (Tfh)-like cells, causes severe colitis in animal models, and is abundantly found in peripheral blood of IBD patients. Because Tfh-like cells are immune-memory cells with highly flexible secretion of effector molecules and are generated in the intestine, they may contribute significantly to chronic inflammation in IBD. However, the role of Tfh-like cells in intestinal inflammation and the regulatory mechanisms of their function in the intestine have yet to be explored. The objective of this application is to identify the key pathways regulating Tfh-like cell generation and function in the intestine. We have demonstrated that TIR-domain-containing adapter-inducing interferon-β (TRIF), a molecule that is activated by encountering bacteria and viruses, plays an important role in maintaining intestinal homeostasis through direction of T cell activation and function. We have found that TRIF limits the generation of Tfh-like cells and T cell flexibility of effector molecule secretion in the intestine through the pathways induced by four key molecules; IFNAR, IL27, STAT1, and STAT3. Impairment of TRIF amplifies Tfh-like cell generation and plasticity, and increased levels of TRIF results in suppression of Tfh-like number and flexibility. Genetic studies have identified that the abnormalities in the IFNAR, IL27, STAT1, and STAT3 genes are often found in Crohn's disease (CD) patients. Therefore, through the following three aims, we would like to address our hypothesis that impairment of the TRIF-mediated pathways allows increased generation of functionally flexible Tfh-like cells that contribute to chronic inflammation in CD, particularly in patients with genetic variants in the IL27, IFNAR, STAT1, and STAT3 genes. Our specific aims are: (1). Determine the mechanism by which Tfh-like cells perpetuate destructive inflammation in the intestine. (2). Determine the mechanisms by which TRIF regulates pathogenic Tfh-like cell generation. (3). Determine the functional consequence of genetic variants within TRIF-mediated pathways in the generation of pathogenic Tfh-like cells in patients with CD. Understanding target pathways affecting the generation of highly aggressive T cells may suggest novel approaches, such as precision medicine, in the management of the subsets of IBD patients in which inflammation is caused by these T cells. The outcome of this project will be novel insight into the essential regulatory mechanisms of highly aggressive T cell populations, which is expected to have a major impact in our understanding of mucosal immunology, as well as in the future therapy of many chronic inflammatory diseases including IBD.

广泛的研究表明，一种对肠道细菌有反应的侵袭性粘膜T细胞亚群， 在炎症性肠病（IBD）的病因中起重要作用。这些攻击性T细胞被认为 作为外周血中的免疫记忆细胞而长寿，并有助于慢性化和复发。 疾病有证据进一步表明，一种灵活分泌不同效应分子的T细胞， 有助于IBD的复杂发病机制。另一种T细胞亚群，T滤泡辅助细胞（Tfh）样细胞， 在动物模型中引起严重的结肠炎，并且在IBD患者的外周血中大量发现。因为 tfh样细胞是免疫记忆细胞，具有高度灵活的效应分子分泌， 肠，他们可能有助于显着慢性炎症IBD。然而，Tfh样细胞的作用 在肠道炎症中的作用及其在肠道中功能的调节机制还有待研究。 探讨了本申请的目的是鉴定调节Tfh样细胞生成的关键途径， 在肠道中发挥作用。我们已经证明了含有TIR结构域的衔接子诱导的干扰素-β （TRIF）是一种通过遇到细菌和病毒而被激活的分子， 通过指导T细胞活化和功能来维持肠道内稳态。我们发现TRIF 限制了Tfh样细胞的产生和T细胞在肠中分泌效应分子的灵活性， 由四种关键分子诱导的途径; IFNAR，IL 27，STAT 1和STAT 3。TRIF放大的损害 Tfh样细胞的生成和可塑性，以及TRIF水平的增加导致Tfh样细胞数量的抑制 和灵活性。遗传学研究已经确定IFNAR、IL 27、STAT 1和STAT 3的异常是由基因突变引起的。 克罗恩病（CD）患者中经常发现这种基因。因此，通过以下三个目标， 我想解决我们的假设，即TRIF介导的途径的损害允许增加的产生， 功能灵活的Tfh样细胞，有助于CD中的慢性炎症，特别是在患有 IL 27、IFNAR、STAT 1和STAT 3基因中的遗传变异。我们的具体目标是：（1）。确定 Tfh样细胞使肠道中的破坏性炎症永久化的机制。（二）、确定 TRIF调节致病性Tfh样细胞生成的机制。（三）、确定函数 TRIF介导途径中遗传变异在致病性Tfh样细胞产生中的作用 在CD患者中。了解影响高度侵袭性T细胞生成的靶途径可能 提出了新的方法，如精确医学，在IBD患者的亚群管理， 炎症是由这些T细胞引起的该项目的成果将是对 高度侵袭性T细胞群的基本调节机制，预计将对T细胞群的功能产生重大影响。 这对我们理解粘膜免疫学，以及未来治疗许多慢性 炎症性疾病，包括IBD。

项目成果

TRIF mobilizes unique primary defense against Gram-negative bacteria in intestinal interface.

TRIF 在肠道界面动员针对革兰氏阴性菌的独特初级防御。

• DOI: 10.4161/gmic.20873
• 发表时间: 2012
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Sotolongo,John;Kanagavelu,Saravana;Hyun,Jinhee;Ruiz,Jose;Fukata,Masayuki
• 通讯作者: Fukata,Masayuki

Systemic Activation of TLR3-Dependent TRIF Signaling Confers Host Defense against Gram-Negative Bacteria in the Intestine.

• DOI: 10.3389/fcimb.2015.00105
• 发表时间: 2015
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Ruiz J;Kanagavelu S;Flores C;Romero L;Riveron R;Shih DQ;Fukata M
• 通讯作者: Fukata M

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens.

含有 TIR 结构域的接头诱导 β 干扰素 (TRIF) 介导针对细菌病原体的免疫记忆。

• DOI: 10.1128/iai.00674-15
• 发表时间: 2015
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Kanagavelu,Saravana;Flores,Claudia;Termini,JM;Romero,Laura;Riveron,Reldy;Ruiz,Jose;Arditi,Moshe;Schesser,Kurt;Fukata,Masayuki
• 通讯作者: Fukata,Masayuki

A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses.

• DOI: 10.1016/j.micinf.2012.10.011
• 发表时间: 2013-01
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Hyun J;Kanagavelu S;Fukata M
• 通讯作者: Fukata M

TIR-domain-containing adapter-inducing interferon-β (TRIF) regulates Th17-mediated intestinal immunopathology in colitis.

• DOI: 10.1038/mi.2014.67
• 发表时间: 2015-03
• 期刊: Mucosal immunology
• 影响因子: 8