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）道是一个衬有单层上皮的大表面，该表面暴露 饮食中的数万亿微生物和无害物质。最大的免疫收集 体内的细胞是该单层上皮的基础，并监视腔内含量 保持稳态中对饮食和共生抗原的耐受性，同时保留 在感染过程中快速诱导病原体免疫的能力。虽然取得了巨大进展 在阐明特定免疫细胞亚群，细胞因子和其他因素的作用方面做出的 促进耐受性或免疫力，该过程与肠道的固有，使免疫系统能够 从稳态中的绝大部分耐受性张力转变为炎症反应 在感染期间，我们的理解仍然是一个差距。最近，我们发现了抑制 小肠（Si）中的杯状细胞相关抗原通道（GAP）迅速移动 免疫原理远离耐受性，并促进炎症TH17的快速诱导 在没有感染或受伤的情况下反应。我们假设抑制间隙是一个 对肠道感染的生理反应本身就促进了Th17的产生 细胞和炎症细胞因子，并将免疫系统的音调转移到耐受性 面向免疫。通过在没有肠道感染或受伤的情况下研究这一过程，我们可以 病原体的脱节贡献和对内在炎症反应的损伤 肠道生态系统的特性促进了从耐受性转向促炎状态的转变。 了解肠道的内在特性，可以快速生成保护性 回应可以提供新的方法来治疗肠道感染并洞悉 肠道慢性炎性疾病的发病机理。我们假设当Si间隙 受到抑制，其他途径接管了Th17细胞的发展和/或扩展 特定于饮食，微生物和/或自我抗原，这将免疫系统的音调转移到 在肠道感染和/或受伤期间提供增强的保护。探讨这一假设我们 提出以下具体目标：在AIM 1中，我们将确定导致TH17的早期事件 Si GAP抑制后的扩展，在AIM 2中，我们将定义 在AIM 3中抑制Si间隙时扩展的Th17细胞，我们将确定是否抑制 SI间隙在肠道感染模型中具有保护性，并且对Si的不适当抑制是否 缺口增强了肠道炎症性疾病。

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