Molecular mechanisms underlying HIV related intestinal epithelial barrier dysfunction

HIV相关肠上皮屏障功能障碍的分子机制

• 批准号: 10630643
• 负责人: Kathleen L. Collins
• 金额: $ 10.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630643
• 关键词: Cells; Chronic; Data; Defect; Development; Epithelial; Epithelial Attachment; Exposure to; Functional disorder; HIV; HIV-1; Health; Immune; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intercellular Junctions; Intestinal permeability; Intestines; Link; Mediator of activation protein; Molecular; Morbidity - disease rate; Pathology; Permeability; Persons; Play; Proteins; Research; Role; Signal Transduction; T-Lymphocyte; Work; antiretroviral therapy; cytokine; improved; injury and repair; intestinal barrier; intestinal epithelium; migration; novel therapeutics; parent grant; repair function; repaired; wound healing

Abstract Compromised intestinal permeability leads to release of epithelial cytokines and antigenic exposure to underlying immune cells. Cytokine release by immune cells in turn perturbs intercellular junction proteins that are crucial for formation of an intact intestinal epithelial barrier. Our data suggest that co-incubation of IECs with HIV-1 infected T cells results in a Nef dependent loss of IEC barrier integrity due to increased epithelial expression of TNFa. Past studies, including work from our group, suggest that pro-inflammatory cytokines disrupt IEC function with preliminary data indicating that TNFa plays an important role HIV-associated intestinal pathology. Interestingly, our research has identified pro-repair functions of TNFa in wounded IEC. At initial glance, intestinal epithelial barrier disruption and enhanced wound repair seem disconnected and even contradictory, but these effects may be explained by signaling mechanisms that result in loosening of epithelial junctions to enhance migration to repair injuries resulting from the inflammatory response. Thus, a leaky barrier as well as increased migration of IEC are interconnected functions triggered by soluble mediators such as TNFa. As the parent grant focuses on barrier dysfunction, this supplemental proposal aims to look at the complementary effects of inflammatory mediators on IEC migration as it relates to repair. The overarching hypothesis is that cytokines such as TNFa impair barrier by altering expression of junctional proteins which in turn increases permeability while promoting IEC migration

摘要 受损的肠通透性导致上皮细胞因子的释放和抗原暴露于潜在的 免疫细胞免疫细胞释放的细胞因子反过来干扰细胞间连接蛋白，这些蛋白对免疫细胞的功能至关重要。 形成完整的肠上皮屏障。我们的数据表明，IEC与HIV-1感染者共孵育， T细胞导致IEC屏障完整性的Nef依赖性丧失，这是由于TNF α的上皮表达增加。 过去的研究，包括我们小组的工作，表明促炎细胞因子破坏IEC功能， 初步数据表明TNF α在HIV相关的肠道病理学中起重要作用。有趣的是， 我们的研究已经确定了TNF α在受伤IEC中的促修复功能。乍一看，肠上皮细胞 屏障破坏和增强伤口修复似乎是脱节的，甚至是矛盾的，但这些作用可能 可以通过导致上皮连接松动以增强迁移到 修复炎症反应导致的损伤。因此，泄漏的屏障以及增加的 IEC是由可溶性介质如TNF α触发的相互关联的功能。由于家长补助金的重点是 屏障功能障碍，这一补充建议的目的是看看炎症的互补作用， 调解员就IEC迁移问题进行调解，因为这与维修有关。最重要的假设是细胞因子如TNF α 通过改变连接蛋白的表达来损害屏障，从而增加渗透性，同时促进 IEC迁移