Inflammatory cross-talk between skin and gut

项目总结/摘要 炎症性肠病经常并发皮肤疾病。不知道为什么 皮肤的表面上皮组织的疾病影响疾病的严重性， 肠道的屏障上皮细胞这项提议将检验中心假设，即"煽动性的相声" 透明质酸（HA）的释放是从细胞外基质释放透明质酸（HA）的结果。 皮肤的基质，然后促进肠粘膜下层的反应性脂肪生成。反应性 脂肪形成是一种新近认识到的皮肤和肠道的先天免疫反应， 抗菌防御我们的初步数据将显示，皮肤损伤，或透明质酸酶的靶向表达， 在皮肤中，对肠道基质有重大影响，导致肠道炎症和粪便的改变。 微生物组我们提出的解释这种情况发生的机制围绕着我们的发现，即HA是 是粘膜下肠成纤维细胞分化为脂肪细胞的关键。HA片段 在皮肤中产生的循环到肠道，刺激脂肪生成，并诱导转录变化， 前脂肪细胞基质细胞分化为脂肪细胞，然后释放抗菌剂， 改变肠道免疫状态的肽和脂肪因子。因此，我们的中心假设是， 通过HA片段刺激脂肪细胞的能力调节肠道中宿主的防御 分化这项建议将测试这一假设，仔细定义脂肪形成对局部的影响， 宿主防御并定义负责这些观察的机制。这些数据对于 为肠道炎症开发新的创新疗法。

Project Summary/Abstract Inflammatory bowel diseases are frequently complicated by diseases of the skin. It is not understood why disease of the surface epithelial tissues of the skin influences the severity of disease of the very different barrier epithelia in the gut. This proposal will test the central hypothesis that the “inflammatory cross” talk between skin and the intestine is a consequence of release of hyaluronic acid (HA) from the extracellular matrix of the skin that then promotes reactive adipogenesis of the intestinal submucosa. Reactive adipogenesis is a newly recognized innate immune response in both skin and intestine, and important for antimicrobial defense. Our preliminary data will show that skin injury, or targeted expression of hyaluronidase in the skin, has a major affect on the intestinal stroma, resulting in alterations in gut inflammation and the fecal microbiome. The mechanism we propose to explain how this occurs centers around our discovery that HA is key for the capacity of submucosal intestinal fibroblasts to differentiate into adipocytes. Fragments of HA generated in the skin circulate to the gut to stimulate adipogenesis and induce transcriptional changes in preadipocytes. The stromal cells undergoing differentiation into adipocytes and then release antimicrobial peptides and adipokines that alter the immune status of the intestine. Thus, our central hypothesis is that injury to the skin modulates host defense in the intestine by the capacity of HA fragments to stimulate adipocyte differentiation. This proposal will test this hypothesis, carefully define the influence of adipogenesis on local host defense and define the mechanisms responsible for these observations. This data can be critical toward developing new and innovative treatments for intestinal inflammation.