Epithelial Cell-Derived IL-1-alpha as a Novel Danger Signal in IBD Pathogenesis

上皮细胞衍生的 IL-1-α 作为 IBD 发病机制中的新型危险信号

• 批准号: 8542831
• 负责人: CLAUDIO FIOCCHI
• 金额: $ 32.95万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542831
• 关键词: Acute; Affect; Amplifiers; Applications Grants; Autoimmune Diseases; Binding; Calcium Binding; Cell Death; Cells; Chemotactic Factors; Chronic; Colitis; Disease; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Event; Extracellular Matrix; Extracellular Matrix Degradation; Family; Fibroblasts; Fostering; Goals; HMGB1 Protein; HMGB1 gene; Human; Hyaluronan; Immune; Immune response; Immunity; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Interleukin-1; Intestines; Leukocytes; Ligands; Maintenance; Mediating; Microbe; Molecular; Names; Necrosis; Nucleic Acids; Organ; Pathogenesis; Pathway interactions; Pattern; Prevention; Production; Reaction; Role; S100 Calcium Binding Protein; Series; Signal Transduction; Staging; Sterility; TLR2 gene; TLR4 gene; Testing; Tissues; Toll-like receptors; Uric Acid; base; cell injury; cytokine; extracellular; germ free condition; gut microbiota; in vivo; injured; innovation; insight; macrophage; neutrophil; novel; pathogen; public health relevance; receptor; response

DESCRIPTION (provided by applicant): A fundamental paradigm of IBD pathogenesis is that inflammation results from an inappropriate response to the pathogen-associated molecular patterns (PAMPs) expressed by the gut microbiota. Recent evidence from other immune-mediated disorders indicates that chronic inflammation occurs when PAMP signals are combined with signals derived from tissue damage, the so-called damage-associated molecular patterns (DAMPs). These are released by injured/dead cells and induce a "sterile inflammatory response". DAMPs are numerous, including the high mobility group protein 1 (HMGB1), nucleic acids, uric acid, degradation products of the extracellular matrix, calcium-binding S100 proteins, and many others. DAMPs utilize receptors shared with PAMPs, such as Toll-like receptors (TLRs), but also distinct receptors, co-receptors and accessory molecules to mediate their actions. Some DAMPs have already been identified in IBD, such as HMGB1 and calcium-binding S100 proteins and, therefore, understanding how their signals converge with those coming from PAMPs becomes obviously relevant and will be explored in this proposal. The cytokine IL-1? has been recently identified as a major DAMP released by necrotic cells and is a strong inducer of sterile inflammation. Because the IL-1 cytokine family is involved in IBD, we performed preliminary studies and found that necrotic intestinal epithelial cells release IL-1?, which induces proinflammatory events in the gut. We also found that IL-1? is present in vivo in the epithelium and can trigger experimental colitis. Thus, we propose the novel central hypothesis that epithelial cell-derived IL-1? is a major intestinal DAMP and represents a novel component of IBD pathogenesis. This hypothesis will be tested by 3 specific aims: Aim 1. Characterize the response of human immune and non-immune cells to necrotic cell-derived IL-1? alone and in combination with other DAMPs and PAMPs. Aim 2. Determine the mechanisms by which necrotic cell-derived IL-1? regulates the inflammatory response. Aim 3. Explore the role of necrotic cell-derived IL-1? in induction and modulation of intestinal inflammation in vivo. The innovative concept that epithelial-derived IL-1? can mediate inflammation alone or in association with PAMPs would create a paradigm shift in our current understanding of IBD pathogenesis. Additionally, interfering with the DAMP function of IL-1? may generate new insights into how to modulate intestinal immunity and inflammation.

描述(申请人提供)：IBD发病机制的一个基本范式是，炎症是由肠道微生物区系表达的病原体相关分子模式(PAMP)的不适当反应引起的。最近来自其他免疫介导性疾病的证据表明，当PAMP信号与来自组织损伤的信号相结合时，慢性炎症就会发生，即所谓的损伤相关分子模式(DAMP)。这些物质由受伤/死亡的细胞释放，并引发“无菌炎症反应”。阻滞剂种类繁多，包括高迁移率族蛋白1(HMGB1)、核酸、尿酸、细胞外基质降解产物、钙结合S100蛋白等。DAMP利用与PAMP共享的受体，如Toll样受体(TLRs)，但也利用不同的受体、辅助受体和辅助分子来调节它们的活动。已经在IBD中发现了一些DAMP，如HMGB1和钙结合S100蛋白，因此，了解它们的信号如何与来自PAMP的信号汇聚变得明显相关，并将在本提案中进行探索。细胞因子IL-1？最近被确认为一种由坏死细胞释放的主要湿气，是无菌炎症的强烈诱因。由于IL-1细胞因子家族参与了IBD，我们进行了初步研究，发现坏死肠上皮细胞释放IL-1β，从而在肠道内引发促炎事件。我们还发现IL-1？在体内存在于上皮细胞中，并可引发实验性结肠炎。因此，我们提出了一个新的中心假设，即上皮细胞来源的IL-1？是一种主要的肠道湿气，代表了IBD发病机制的一个新组成部分。这一假设将通过三个特定的目标来检验：目标1.描述人类免疫和非免疫细胞对坏死细胞来源的IL-1的反应？单独或与其他阻尼剂和PAMP一起使用。目的2.确定坏死细胞来源的IL-1的机制？调节炎症反应。目的3.探讨坏死细胞来源的IL-1的作用。在体内诱导和调节肠道炎症。上皮源性IL-1的创新概念？能否单独或与PAMP联合介导炎症将改变我们目前对IBD发病机制的理解。此外，干扰IL-1的潮湿功能？可能会对如何调节肠道免疫和炎症产生新的见解。