Cell interactions in the inflammed intestinal mucosa

发炎肠粘膜中的细胞相互作用

• 批准号: 8447451
• 负责人: CLAUDIO FIOCCHI
• 金额: $ 30.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447451
• 关键词: Acute; Adhesions; Bacteria; Cell Communication; Cells; Characteristics; Chronic; Crohn' s disease; Development; Endothelial Cells; Epigenetic Process; Fibroblasts; Funding; Future; Gastrointestinal tract structure; Gene Expression; Genomics; Human; Immune; Immune response; Immunity; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Mucosa; Intestines; Investigation; Knowledge; Laboratories; Leukocytes; Ligands; Maintenance; Mediating; Mediator of activation protein; Mesenchymal; Microbial Genetics; Modification; Molecular; Mucosal Immunity; Mucositis; Mucous Membrane; Natural Immunity; Pathogenesis; Pathway interactions; Permeability; Play; Process; Production; Regulation; Role; Signal Pathway; Stimulus; Testing; Therapeutic Intervention; Ulcerative Colitis; absorption; angiogenesis; base; cell type; cytokine; histone modification; immune activation; microbial; novel; public health relevance; receptor; receptor expression; response; synergism

DESCRIPTION (provided by applicant): Multiple cell types are involved in the development and maintenance of chronic inflammation. This is also true in inflammatory bowel disease (IBD), where long-standing activation of immune and nonimmune cells results in severe structural and functional abnormalities. Studies performed during the last funding period have defined the phenotypic and functional characteristics of two types of nonimmune intestinal cells, human intestinal fibroblasts (HIF) and microvascular endothelial cells (HIMEC), and assessed their interaction with mucosal immune cells. The results demonstrated that both HIF and HIMEC play an active role in immunity and inflammation through interaction with immune cells and cytokine production. These observations strongly support the concept that immune-nonimmune cell interactions are critically involved in the pathogenesis of IBD. Investigation of genetic, microbial, and immune factors has recently shown the key role of innate immunity in IBD, and that the receptors mediating such innate immune responses are also expressed by nonimmune cells, allowing them to contribute to mucosal immunity and inflammation. This contribution is likely to be enhanced in IBD due to the increased absorption of bacterial products, which can activate HIF and HIMEC expressing Toll- like (TLR) and NOD-like (NLR) receptors, as shown in our preliminary results. Therefore, based on these premises, we propose to test the following central hypothesis: bacterial products can directly activate mesenchymal and endothelial cells and create self-sustaining stimulatory circuits that amplify and prolong gut inflammation. This hypothesis will be tested by investigating: 1) the expression, modulation and functional response of TLRs and NLRs in HIF and HIMEC; 2) the response of HIF and HIMEC to combined microbial and inflammatory stimuli; 3) the effect of bacterial product stimulation on HIF and HIMEC proinflammatory activity; 4) the epigenetic regulation of TLR- and NLR-induced gene expression in HIF and HIMEC. The results will expand knowledge of the mechanisms of chronic gut inflammation and may identify novel pro-inflammatory pathways as potential targets of future therapeutic intervention in IBD.

描述（由申请人提供）：多种细胞类型参与慢性炎症的发展和维持。炎症性肠病（IBD）也是如此，免疫和非免疫细胞的长期激活会导致严重的结构和功能异常。上一个资助期间进行的研究确定了两种非免疫肠道细胞——人肠道成纤维细胞（HIF）和微血管内皮细胞（HIMEC）的表型和功能特征，并评估了它们与粘膜免疫细胞的相互作用。结果表明，HIF 和 HIMEC 通过与免疫细胞相互作用和细胞因子产生在免疫和炎症中发挥积极作用。这些观察结果有力地支持了免疫-非免疫细胞相互作用在 IBD 发病机制中至关重要的概念。最近对遗传、微生物和免疫因素的研究表明，先天免疫在 IBD 中发挥着关键作用，并且介导这种先天免疫反应的受体也由非免疫细胞表达，从而使它们有助于粘膜免疫和炎症。正如我们的初步结果所示，由于细菌产物的吸收增加，这种作用在 IBD 中可能会增强，细菌产物可以激活表达 Toll 样 (TLR) 和 NOD 样 (NLR) 受体的 HIF 和 HIMEC。因此，基于这些前提，我们建议测试以下中心假设：细菌产物可以直接激活间充质和内皮细胞，并创建自我维持的刺激回路，从而放大和延长肠道炎症。该假设将通过以下研究进行检验：1）HIF 和 HIMEC 中 TLR 和 NLR 的表达、调节和功能反应； 2）HIF和HIMEC对微生物和炎症联合刺激的反应； 3）细菌产物刺激对HIF和HIMEC促炎活性的影响； 4）HIF和HIMEC中TLR和NLR诱导的基因表达的表观遗传调控。这些结果将扩大对慢性肠道炎症机制的了解，并可能确定新的促炎症途径作为未来 IBD 治疗干预的潜在目标。