Gut Intrinsic Inflammatory Responses

肠道内在炎症反应

• 批准号: 10614624
• 负责人: CHYI S HSIEH
• 金额: $ 44.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-26 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614624
• 关键词: Address; Antigen-Presenting Cells; Antigens; Autoantigens; Automobile Driving; Biological Assay; Cell Differentiation process; Cells; Chemicals; Collection; Development; Diet; Early identification; Ecosystem; Epithelial Cells; Epithelium; Equilibrium; Event; Exposure to; Flow Cytometry; Gastrointestinal tract structure; Gene Expression; Generations; Gnotobiotic; Goblet Cells; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunologics; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Lamina Propria; Maps; Microbe; Modeling; Monitor; Mucous body substance; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Physiological; Process; Property; Regulatory T-Lymphocyte; Reporter; Role; Severities; Small Intestinal Goblet Cell; Small Intestines; Specificity; Surface; T-Lymphocyte; T-cell receptor repertoire; Transgenic Mice; adaptive immune response; chronic inflammatory disease; cytokine; dietary; enteric infection; gut inflammation; in vivo; insight; intestinal epithelium; microbial; microbiota; microorganism antigen; novel strategies; pathogen; response; transdifferentiation

The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed to trillions of microbes and innocuous substances from the diet. The largest collection of immune cells in the body underlies this single layer epithelium and monitors the luminal contents to maintain tolerance to dietary and commensal antigens in the steady-state while retaining the ability to rapidly induce immunity to pathogens during infection. While great progress has been made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17 responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a physiologic response to enteric infection, which in and of itself, promotes the generation of Th17 cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance toward immunity. By studying this process in the absence of enteric infection or injury we can disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state. Understanding intrinsic properties of the gut that allows the rapid generation of protective responses could provide new approaches to treat enteric infections and provide insight into the pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs are inhibited, other pathways take over driving the development and/or expansion of Th17 cells specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to provide enhanced protection during enteric infection and/or injury. To explore this hypothesis we propose the following specific aims: In aim 1 we will identify the early events resulting in Th17 expansion following SI GAP inhibition, in aim 2 we will define the origins and specificities of the Th17 cells that expand when SI GAPs are inhibited in aim 3 we will determine if the inhibition of SI GAPs is protective in models of enteric infection and whether inappropriate inhibition of SI GAPs potentiates intestinal inflammatory disease.

胃肠道 (GI) 是一个很大的表面，内衬有暴露的单层上皮 饮食中数万亿微生物和无毒物质。最大的免疫集合 体内的细胞位于单层上皮的下方，并监测管腔内容物 保持对饮食和共生抗原的耐受性处于稳态，同时保留 在感染过程中快速诱导对病原体的免疫力的能力。虽然已经取得了巨大的进步 阐明特定免疫细胞亚群、细胞因子和其他因素的作用 促进耐受性或免疫力，这是肠道固有的、使免疫系统发挥作用的过程 从稳态的压倒性耐受性基调转变为炎症反应 在感染期间，我们的理解仍然存在差距。最近，我们发现抑制 小肠 (SI) 中的杯状细胞相关抗原通道 (GAP) 迅速改变 免疫张力远离耐受性并促进炎症 Th17 的快速诱导 在没有感染或受伤的情况下的反应。我们假设 GAP 的抑制是 对肠道感染的生理反应，其本身促进 Th17 的产生 细胞和炎症细胞因子，并使免疫系统的基调偏离耐受性 走向免疫力。通过在没有肠道感染或损伤的情况下研究这个过程，我们可以 将病原体和损伤对炎症反应的贡献与内在因素分开 肠道生态系统的特性促进从耐受状态向促炎症状态的转变。 了解肠道的内在特性，可以快速产生保护性物质 应对措施可以提供治疗肠道感染的新方法并提供对肠道感染的深入了解 肠道慢性炎症性疾病的发病机制。我们假设当 SI GAP 受到抑制，其他途径接管驱动 Th17 细胞的发育和/或扩增 特异性针对饮食、微生物和/或自身抗原，从而将免疫系统的基调转变为 在肠道感染和/或损伤期间提供增强的保护。为了探索这个假设，我们 提出以下具体目标： 在目标 1 中，我们将确定导致 Th17 的早期事件 SI GAP 抑制后的扩展，在目标 2 中，我们将定义 SI GAP 抑制的起源和特异性 在目标 3 中，当 SI GAP 受到抑制时，Th17 细胞会扩张，我们将确定是否抑制 SI GAPs 在肠道感染模型中具有保护作用，以及是否不适当抑制 SI GAP 会加剧肠道炎症性疾病。

项目成果

Identification of Gut Bacteria such as Lactobacillus johnsonii that Disseminate to Systemic Tissues of Wild Type and MyD88-/- Mice.

• DOI: 10.1080/19490976.2021.2007743
• 发表时间: 2022-01
• 期刊: Gut microbes
• 影响因子: 12.2
• 作者: Udayan S;Stamou P;Crispie F;Hickey A;Floyd AN;Hsieh CS;Cotter PD;O'Sullivan O;Melgar S;O'Toole PW;Newberry RD;Rossini V;Nally K
• 通讯作者: Nally K

Small Intestinal Goblet Cells Control Humoral Immune Responses and Mobilization During Enteric Infection.

小肠杯状细胞控制肠道感染期间的体液免疫反应和动员。

• DOI: 10.1101/2024.01.06.573891
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Kulkarni,DeveshaH;Talati,Khushi;Joyce,ElisabethL;Kousik,Hrishi;Harris,DaliaL;Floyd,AlexandriaN;Vavrinyuk,Vitaly;Barrios,Bibianna;Udayan,Sreeram;McDonald,Keely;John,Vini;Hsieh,Chyi-Song;Newberry,RodneyD
• 通讯作者: Newberry,RodneyD