Endogenous TLR1 signals prevent uncontrolled innate immunity in the colon

内源性 TLR1 信号可防止结肠中不受控制的先天免疫

• 批准号: 9027838
• 负责人: R William DePaolo
• 金额: $ 6.48万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-12-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027838
• 关键词: Affect; Age; Automobile Driving; Bacteria; Bacterial Infections; Bone Marrow; Cells; Cessation of life; Child; Childhood; Chimera organism; Chronic; Colon; Communication; Complex; Conflict (Psychology); Data; Development; Diarrhea; Disease; Enteral; Environment; Epithelium; Eukaryotic Cell; European; Exhibits; Food; Genes; Genetic; Genetic Polymorphism; Goals; Goblet Cells; Health; Home environment; Homeostasis; Human; Immune response; Immune system; Immunity; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interleukin-1 beta; Interleukin-17; Intestinal Diseases; Intestines; Lamina Propria; Lead; Lymphoid Cell; Maintenance; Mediator of activation protein; Modeling; Mucosal Immunity; Mucous body substance; Mus; Mutation; Natural Immunity; Normal Cell; Organ; Outcome; Paneth Cells; Pathology; Patients; Permeability; Phenotype; Play; Production; Proteins; Receptor Signaling; Regulation; Relapse; Reporting; Research; Role; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Site; Surface; TLR1 gene; TLR2 gene; Therapeutic; Toll-like receptors; Viral; Work; absorption; antimicrobial; base; cell type; colitis associated cancer; commensal microbes; cytokine; enteric pathogen; genome wide association study; injury and repair; innovation; interleukin-22; interleukin-23; microbial; microbiota; mouse model; neutrophil; novel; pathogen; pediatric patients; prevent; receptor; research study; response; transcription factor

 DESCRIPTION (provided by applicant): The intestine is a complex organ home to one of our body's largest immune system networks, 100 trillion commensal bacteria, and a variety of specialized eukaryotic cells, such as epithelium, Paneth cells and mucus- producing goblet cells. A high antigenic burden in the intestine exists because it is a common entry site for pathogens, the site for absorption of food proteins and the high number of commensal bacteria. Dysregulation of the immune responses can lead to disease such as inflammatory bowel disease (IBD) or colitis-associated cancers. In order to prevent aberrant immune responses communication and regulation between these compartments is essential. The close proximity of the microbial world to the human cells of our intestine suggest that innate receptors, such as Toll-like Receptors (TLR), which recognize conserved microbial motifs, may play an essential role in regulating homeostasis and inflammation. Our previous work has identified TLR1 as a critical mediator of intestinal immunity during pathogenic infection. Further, we have found that a single nucleotide polymorphism in TLR1, which abrogates surface expression and signaling, is associated with pediatric IBD. Further this mutation impacts disease severity and response to immune-therapies. Intriguingly, we have found that naïve mice deficient for TLR1 signaling produce elevated levels of the pro-inflammatory innate cytokines IL-23 and IL-1ß in the colonic lamina propria. IL-23 and IL-1ß are important for the expansion and maintenance of TH17 cells and group 3 innate lymphoid cells (ILC3). We have found that homeostatic levels of TH17 cells are normal, however ILC3 are significantly increased in the colons of TLR1-deficient mice. Importantly ILC have been identified in patients with IBD, though their induction, regulation and role are still unknown. The proposed research will examine the regulation of IL-23 and IL-1ß in the absence of endogenous TLR1 signaling in the colon and how this impacts the development of ILC3. Specifically, we will determine whether IL-1ß and IL-23 are necessary and sufficient for the homeostatic increase in ILC3 and determine the cell types necessary for this increase. We will also determine how the absence of TLR1 signaling in the colon leads to up-regulated IL-23 and IL-1ß. Lastly, as ILC can have both protective and pathogenic roles in the colon, we will examine how ILC induced in the absence of TLR1 signaling impacts intestinal inflammatory responses. The results of these studies will contribute to the understanding how specific TLR1 signals regulate of innate immunity in the colon. Further, as we have identified a mutation in TLR1 signaling in pediatric patients with IBD, a greater understanding of the regulation of innate immunity by TLR1 may lead to the development of individualized therapies or treatments to prevent disease or relapses.

 描述(申请人提供)：肠道是一个复杂的器官，拥有我们身体最大的免疫系统网络之一，100万亿个共生细菌，以及各种专门的真核细胞，如上皮细胞、潘氏细胞和产生粘液的杯状细胞。肠道中存在很高的抗原负担，因为它是病原体的常见进入部位，食物蛋白质的吸收部位，以及大量共生细菌。免疫反应的失调会导致炎症性肠病(IBD)或结肠炎相关癌症等疾病。为了防止异常的免疫反应，这些间隔之间的沟通和调节是必不可少的。微生物世界与人类肠道细胞的密切联系表明，固有受体，如Toll样受体(TLR)，识别保守的微生物基序，可能在调节体内平衡和炎症方面发挥重要作用。我们以前的工作已经确定TLR1是致病感染过程中肠道免疫的关键介质。此外，我们还发现， TLR1的单核苷酸多态取消了表面表达和信号转导，与儿童IBD相关。此外，这种突变还会影响疾病的严重程度和对免疫疗法的反应。有趣的是，我们发现，缺乏TLR1信号的幼稚小鼠在结肠固有层中会产生高水平的促炎天然细胞因子IL-23和IL-1？IL-23和IL-1？对TH17细胞和第3组天然淋巴样细胞(ILC3)的扩增和维持起重要作用。我们发现TH17细胞的动态平衡水平是正常的，而TLR1缺陷小鼠的结肠中ILC3显著增加。重要的是，已经在IBD患者中发现了ILC，尽管它们的诱导、调节和作用尚不清楚。这项拟议的研究将研究在结肠中没有内源性TLR1信号的情况下IL-23和IL-1ç的调节，以及这如何影响ILC3的发展。具体地说，我们将确定IL-1ü和IL-23对于ILC3内环境平衡增加是否必要和充分，并确定这种增加所需的细胞类型。我们还将确定TLR1信号在结肠中的缺失如何导致IL-23和IL-1ç上调。最后，由于ILC在结肠中既有保护作用又有致病作用，我们将研究在缺乏TLR1信号的情况下诱导的ILC如何影响肠道炎症反应。这些研究结果将有助于理解特定的TLR1信号如何调节结肠的先天免疫。此外，由于我们已经在儿童IBD患者中发现了TLR1信号的突变，对TLR1调节天然免疫的更多了解可能会导致个性化治疗或治疗的发展，以防止疾病或复发。