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

描述（由申请人提供）：IBD发病机制的一个基本范式是炎症是由肠道微生物群对病原体相关分子模式（PAMPs）表达的不适当反应引起的。最近来自其他免疫介导疾病的证据表明，当PAMP信号与来自组织损伤的信号结合时，即所谓的损伤相关分子模式（DAMPs），慢性炎症就会发生。这些物质由受伤/死亡细胞释放，并诱导“无菌炎症反应”。阻尼物种类繁多，包括高迁移率基团蛋白1 （HMGB1）、核酸、尿酸、细胞外基质降解产物、钙结合S100蛋白等。DAMPs利用与PAMPs共享的受体，如toll样受体（tlr），以及不同的受体、共受体和辅助分子来介导其作用。一些DAMPs已经在IBD中被发现，如HMGB1和钙结合S100蛋白，因此，了解它们的信号如何与来自PAMPs的信号收敛变得明显相关，并将在本提案中进行探讨。细胞因子IL-1？最近发现它是坏死细胞释放的一种主要的DAMP，是无菌性炎症的强诱导剂。由于IL-1细胞因子家族参与IBD，我们进行了初步研究，发现坏死的肠上皮细胞释放IL-1？它会在肠道中引发促炎事件。我们还发现IL-1？存在于体内上皮中，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DAMP，是IBD发病机制的一个新组成部分。这一假设将通过三个具体目标来检验：目标1。表征人类免疫和非免疫细胞对坏死细胞源性IL-1的反应？单独或与其他DAMPs和PAMPs联合使用。目标2。确定坏死细胞衍生IL-1的机制？调节炎症反应。目标3。探讨坏死细胞源性IL-1的作用？体内肠道炎症的诱导和调节。上皮源性IL-1？可以单独或与PAMPs联合介导炎症，将为我们目前对IBD发病机制的理解带来范式转变。此外，干扰IL-1的DAMP功能。可能会对如何调节肠道免疫和炎症产生新的见解。

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. PUBLIC HEALTH RELEVANCE: The proposed studies are aimed at understanding the function of the cytokine IL-1 in intestinal inflammation and how it contributes to the pathogenesis of inflammatory bowel disease (IBD). IL-1 belongs to a group of agents collectively named damage-associated molecular patterns (DAMPs). DAMPs pre-exist in various tissues and organs, but they are normally hidden from the body immune defenses and therefore cause no harm. However, when cells die, DAMPs are released and bind to receptors on a variety of immune and non-immune cells and induce an inflammatory response. The studies proposed in this application are focused on the IL-1? contained in intestinal epithelial cells that is released when these cells are damaged or destroyed. When this occurs IL-1? triggers a strong inflammatory reaction that further damages the intestine and may contribute to perpetuate gut inflammation, as characteristically seen in IBD. In addition to fostering inflammation by itself, I-1? likely interacts with other substances derived from microbes or dead cells, and this combination may amplify or prolong gut inflammation, another aspect that will also be investigated in this grant application.