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

描述（由申请人提供）：IBD发病机制的基本范例是炎症是由对肠道微生物群表达的病原体相关分子模式（PAMP）的不适当反应引起的。来自其他免疫介导的疾病的最新证据表明，当PAMP信号与来自组织损伤的信号（所谓的损伤相关分子模式（DAMP））组合时，发生慢性炎症。这些由受损/死亡细胞释放并诱导“无菌炎症反应”。DAMP有很多，包括高迁移率族蛋白1（HMGB 1）、核酸、尿酸、细胞外基质的降解产物、钙结合S100蛋白等。DAMP利用与PAMP共有的受体，例如Toll样受体（TLR），但也利用不同的受体、共受体和辅助分子来介导它们的作用。已经在IBD中鉴定了一些DAMP，例如HMGB 1和钙结合S100蛋白，因此，了解它们的信号如何与来自PAMP的信号会聚变得明显相关，并将在本提案中进行探索。细胞因子IL-1？最近被鉴定为坏死细胞释放的主要DAMP，并且是无菌炎症的强诱导物。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？，从而在肠道中诱发促炎事件。我们还发现IL-1？存在于体内上皮中，并可引发实验性结肠炎。因此，我们提出了新的中央假说，上皮细胞来源的IL-1？是一种主要的肠道DAMP，代表了IBD发病机制的新组分。这一假设将通过3个具体目标进行检验：目标1。表征人免疫和非免疫细胞对坏死细胞衍生的IL-1的反应？单独或与其它DAMP和PAMP组合。目标二。确定坏死细胞来源的IL-1？调节炎症反应。目标3。探讨坏死细胞来源的IL-1的作用？诱导和调节体内肠道炎症。创新的概念，上皮来源的IL-1？可以单独或与PAMPs联合介导炎症，这将在我们目前对IBD发病机制的理解中产生范式转变。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.