Lipid dysregulation of immune mediated intestinal epithelial healing

免疫介导的肠上皮愈合的脂质失调

• 批准号: 10579908
• 负责人: Andrea Alyssa McAlester
• 金额: $ 15.29万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-07 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579908
• 关键词: Animals; Anti-Inflammatory Agents; Apoptotic; Atherosclerosis; Autoimmune; Autoimmune Diseases; Biological Assay; Body Weight decreased; CD36 gene; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Clinical; Colitis; Cytoprotection; Data; Defect; Development; Diet; Dietary Component; Dietary Fats; Disease; Environment; Environmental Risk Factor; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Fatty acid glycerol esters; Functional disorder; Goblet Cells; Health; High Fat Diet; Immune; Immune response; Immune system; Impairment; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Ingestion; Inhalation; Insulin-Dependent Diabetes Mellitus; Intercellular Junctions; Interleukin-10; Intestinal Diseases; Intestines; Link; Lipids; Lupus; Macrophage; Mediating; Microbe; Molecular; Mus; Pathogenesis; Pathology; Pathway interactions; Penetration; Phase; Physiology; Predisposition; Process; Production; Proliferating; Proteins; Regulation; Resolution; Role; Severities; Signal Pathway; Signal Transduction; Stimulus; Support System; Symptoms; System; Testing; Tight Junctions; Time; Tissues; Weight Gain; chronic inflammatory disease; cytokine; effective therapy; epithelial repair; feeding; food consumption; gut inflammation; gut microbiota; healing; immune function; in vivo; insight; interest; intestinal barrier; intestinal epithelium; intestinal homeostasis; intestinal injury; microbial; mouse model; neutrophil; novel; pathogen; prevent; receptor; repair function; repaired; response; systemic inflammatory response; therapeutic target; tissue injury; tissue repair; tissue-repair responses; uptake; wound healing

Lipid dysregulation of immune mediated intestinal epithelial healing A single layer of epithelial cells protects us from harmful interactions with the intestinal microbiota and harmful agents we inhale and ingest daily. Unresolved damage to this epithelial layer can lead to the development of chronic inflammatory diseases, including inflammatory bowel disease (IBD). High fat diets (HFD) correspond to increased incidence and severity of many chronic inflammatory diseases. Diets high in fat have been demonstrated to directly induce pro-inflammatory functions in macrophages, promoting chronic inflammation. In the intestine, HFD has been shown to decrease barrier function and promote chronic inflammation. However, it’s impact on intestinal immune function and tissue repair processes is less understood. Our immune system supports the proper functioning of tissue barriers. In response to tissue damage, tissue macrophages induce pro-inflammatory immune functions aiding in protection from pathogens. In the resolution phase of this response, these cells produce anti-inflammatory cytokines to dampen inflammation and promote tissue repair. Perturbations to any aspect of this response can lead to ineffective repair of tissue injury and development of inflammation. A key signal involved in this molecular switch of macrophages from pro- to anti-inflammatory responses is clearance of apoptotic cells, specifically apoptotic neutrophils. Defects in this response have been linked to many auto-immune and chronic inflammatory diseases including lupus, type 1 diabetes, atherosclerosis, COPD and cardiovascular disease. Tissue macrophages are important in intestinal homeostasis and their dysfunction is thought to drive disease pathogenesis in IBD. Further, defective barrier repair is seen in intestinal disease, but it is unclear whether defective apoptotic cell clearance by intestinal macrophages is involved and what mechanisms could modulate this process. To determine the impact of HFD on intestinal tissue repair responses, we utilized short-term HFD feeding in the context of mouse models of intestinal injury. Our data demonstrates that HFD increases susceptibility to colitis with increased weightloss, aberrant epithelial cell proliferation, loss of goblet cells and tight junction proteins necessary to prevent microbial penetration into the body. Further, we identified dysregulated immune responses resulting in an inability of intestinal immune cells to properly support barrier function and repair. We also find that HFD alters macrophage responses to and clearance of apoptotic neutrophils. Together, we find that HFD feeding directly promotes altered functions of intestinal immune cells leading to barrier repair defects. These findings led us to hypothesize that dietary lipids directly interfere with apoptotic cell recognition and uptake receptors and activation of downstream pro-repair signaling pathways resulting in dysregulated intestinal barrier repair. This is the basis of my K01 application.

免疫介导的肠上皮愈合的脂质失调 单层上皮细胞保护我们免受与肠道微生物群的有害相互作用， 我们每天吸入和摄入的物质。对这一上皮层的未解决的损伤可导致 慢性炎性疾病，包括炎性肠病（IBD）。高脂饮食（HFD）对应于 许多慢性炎症性疾病的发病率和严重程度增加。高脂肪饮食 证明直接诱导巨噬细胞中的促炎功能，促进慢性炎症。在 在肠道中，HFD已被证明降低屏障功能并促进慢性炎症。然而，在这方面， 它对肠道免疫功能和组织修复过程的影响还不太清楚。 我们的免疫系统支持组织屏障的正常运作。为了应对组织损伤， 组织巨噬细胞诱导促炎性免疫功能，帮助保护免受病原体的侵害。在 在这种反应的消退阶段，这些细胞产生抗炎细胞因子以抑制炎症， 促进组织修复。对这种反应的任何方面的干扰都可能导致组织损伤的无效修复 和炎症的发展。一个关键信号参与了巨噬细胞从亲- 抗炎反应是清除凋亡细胞，特别是凋亡中性粒细胞。网站的缺陷 这种反应与许多自身免疫性和慢性炎症性疾病有关，包括1型狼疮 糖尿病、动脉粥样硬化、COPD和心血管疾病。组织巨噬细胞在肠道中是重要的 体内平衡及其功能障碍被认为是IBD疾病发病机制的驱动因素。此外，有缺陷的屏障 在肠道疾病中可以看到修复，但尚不清楚肠上皮细胞对凋亡细胞的清除是否有缺陷， 巨噬细胞的参与和什么机制可以调节这一过程。 为了确定HFD对肠组织修复反应的影响，我们利用短期HFD喂养 在肠道损伤的小鼠模型的背景下。我们的数据表明，HFD增加了对 结肠炎伴体重减轻增加、上皮细胞异常增殖、杯状细胞和紧密连接丢失 防止微生物侵入体内所必需的蛋白质。此外，我们发现了免疫调节失调， 免疫应答导致肠道免疫细胞不能适当地支持屏障功能和修复。我们 还发现HFD改变了巨噬细胞对凋亡中性粒细胞的反应和清除。我们一起发现 HFD喂养直接促进肠道免疫细胞功能的改变，导致屏障修复缺陷。 这些发现使我们假设膳食脂质直接干扰凋亡细胞的识别和摄取 受体和下游促修复信号通路的激活导致肠屏障失调 修复.这是我的K01应用程序的基础。