Inflammatory cross-talk between skin and gut

皮肤和肠道之间的炎症串扰

• 批准号: 10356934
• 负责人: Richard L Gallo
• 金额: $ 67.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356934
• 关键词: Address; Adipocytes; Affect; Allergic inflammation; Catabolism; Cells; Chemicals; Clinical; Communication; Cutaneous; Data; Dermal; Dermis; Digestion; Disease; Epithelial; Estrogen Receptors; Extracellular Matrix; Fatty acid glycerol esters; Fibroblasts; Genetic Transcription; Gnotobiotic; Goals; Host Defense; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Immune; Immune system; Immunity; In Vitro; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Innate Immune Response; Intervention; Intestines; Measures; Mediating; Modeling; Mucous Membrane; Mus; Names; Outcome Measure; Patients; Phenotype; Process; Role; Salmonella; Series; Severities; Severity of illness; Skin; Skin Tissue; Skin injury; Staphylococcus aureus; Stimulus; Stromal Cells; Submucosa; Surface; System; Testing; Work; adipocyte differentiation; adipokines; antimicrobial; antimicrobial peptide; cathelicidin; clinically relevant; experimental study; fecal microbiome; genetic approach; gut inflammation; human tissue; immune function; immunological status; in vitro Model; injured; innovation; intestinal injury; lipid biosynthesis; microbiome; precursor cell; receptor; response; skin disorder; wound

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.

项目概要/摘要 炎症性肠病经常并发皮肤疾病，目前尚不清楚原因。 皮肤表面上皮组织的疾病影响不同疾病的严重程度 该提案将检验“炎症交叉”对话的中心假设。 皮肤和肠道之间的透明质酸（HA）从细胞外释放的结果 皮肤基质，然后促进肠粘膜下层的反应性脂肪生成。 脂肪生成是皮肤和肠道中新认识的先天免疫反应，对于 我们的初步数据将表明，皮肤损伤或透明质酸酶的靶向表达。 在皮肤中，对肠基质有重大影响，导致肠道炎症和粪便的改变 我们建议解释这一现象如何发生的机制以我们的发现为中心：HA 是 粘膜下肠成纤维细胞分化成脂肪细胞的能力的关键。 皮肤中产生的物质重新进入肠道，刺激脂肪生成并诱导转录变化 前脂肪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，我们的中心假设是损伤。 皮肤通过 HA 片段刺激脂肪细胞的能力来调节肠道内的宿主防御 该提案将检验这一假设，仔细定义脂肪生成对局部的影响。 宿主防御并定义负责这些观察的机制，这些数据对于这些观察至关重要。 开发针对肠道炎症的创新疗法。