Inflammatory cross-talk between skin and gut

项目摘要/摘要 炎症性肠病常常并发皮肤病。目前还不清楚为什么 皮肤表面上皮组织的疾病影响疾病的严重程度截然不同 肠道中的屏障上皮细胞。这一提议将检验“煽动性的相声”这一中心假设。 皮肤和肠道之间是细胞外释放透明质酸(HA)的结果 皮肤基质，然后促进肠道粘膜下层的反应性脂肪生成。反应性 脂肪生成是一种新发现的皮肤和肠道的先天性免疫反应，对 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，对肠道间质有重大影响，导致肠道炎症和粪便的变化。 微生物组。我们提出的解释这种情况发生的机制是围绕着我们发现HA是 肠粘膜下成纤维细胞分化为脂肪细胞能力的关键。HA的碎片 在皮肤中产生，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后释放抗菌药物 能改变肠道免疫状态的多肽和脂肪因子。因此，我们的中心假设是伤害 皮肤通过HA片段刺激脂肪细胞调节肠道宿主防御 差异化。这项提议将检验这一假说，仔细定义脂肪生成对局部 主持防御并定义负责这些观察的机制。这些数据可能对 开发肠道炎症的新的和创新的治疗方法。

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.