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The pathogenic roles of GSDMD-dependent gut epithelium extracellular vesicles in IBD

GSDMD依赖性肠上皮细胞外囊泡在IBD中的致病作用

基本信息

批准号：
10386894
负责人：
Theresa Torres Pizarro
金额：
$ 42.05万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386894
关键词：
Address Affect Anti-Tumor Necrosis Factor Therapy Area Binding Proteins Biogenesis Biological Response Modifiers Biopsy CDC37 gene Caspase Cells Cellular Stress Chronic Clinical Colitis Colon Colonic inflammation Communications Media Complex Data Detection Disease Environment Environmental Risk Factor Epithelial Epithelial Cells Etiology Family Family member Granulocyte-Macrophage Colony-Stimulating Factor Human Immune Immune response Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferon Type II Interferons Interleukin-1 Interleukin-18 Intestinal Content Knockout Mice Length Lipid Binding Lytic Mediating Modeling Molecular Molecular Chaperones Mucous Membrane Mus N-terminal Nonlytic Organoids Pathogenesis Pathogenicity Pathway interactions Patients Persons Play Polyubiquitination Preventive measure Production Proteomics Resistance Role Signal Transduction Source Specimen Stimulus Surface T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Tissues Treatment Failure United States Vesicle adaptive immune response autocrine base cytokine dextran sulfate sodium induced colitis exosome extracellular vesicles gastrointestinal epithelium gut inflammation injured insight intestinal epithelium macrophage member murine colitis novel pre-clinical research public health relevance recruit response success ubiquitin-protein ligase

项目摘要

Abstract Understanding how environmental factors trigger dysregulated immune responses was identified as a key challenge in preclinical research for the pathogenesis of inflammatory bowel disease (IBD). Dysregulated responses to the luminal environment by intestinal epithelial cells (IECs) have been widely postulated to be a driver of IBD. On the other hand, the success of immunomodulatory biologics, such as vedolizumab and ustekinumab, clearly demonstrate the central role of T cells, especially pathogenic T cells, in IBD. However, it remains unclear how IECs convey innate immune detection at mucosal surfaces to adaptive immune responses and subsequent inflammation. Emerging at the center of this sensing function is the inflammasome, which can detect cellular stress and danger signals, such as ATP, found in injured tissues during chronic inflammation. In our quest to understand the role of the inflammasome in IECs, we found that IECs release large amounts of small extracellular vesicles (sEVs) containing polyubiquitinated IL-1 family cytokines, including IL-1 and IL-18, in response to inflammasome activation in a GSDMD-dependent manner. Importantly, IEC-derived sEVs represent a novel form of communication between IECs and T cells. In particular, IL-18 promotes inflammatory pathogenic T cells via induction of IFN? and GM-CSF production. sEVs-derived from inflamed mouse colons exacerbate disease and confer resistance to anti-TNF treatment in a T cell transfer colitis model. Consistently, IECs from biopsies of inflamed areas from IBD patients displayed enhanced capacity to produce sEVs compared to that from non-inflamed areas. Thus, we hypothesize that IEC-derived sEVs play a critical role in IBD pathogenesis by amplifying epithelial inflammatory responses and promoting pathogenic T cells via the release of sEVs containing IL-1 family cytokines, including IL-1 and IL-18, and perhaps IL-33. This application seeks to determine the molecular mechanism(s) that underlie the release of sEVs and assess the importance of sEVs in promoting pathogenic T cells and anti-TNF therapy failure in murine models of colitis and in patient-derived specimens from IBD patients.

摘要