Gut Intrinsic Inflammatory Responses

肠道内在炎症反应

• 批准号: 10456984
• 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/10456984
• 关键词: Address; Antigen-Presenting Cells; Antigens; Autoantigens; Automobile Driving; Biological Assay; Cells; Chemicals; Collection; Development; Diet; Ecosystem; Epithelial; Epithelial Cells; 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; Microbe; Modeling; Monitor; Mucous body substance; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Physiological; Process; Property; Regulatory T-Lymphocyte; Reporter; Role; Severities; 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.

胃肠道是一个由暴露的单层上皮排列的大表面