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Lipid dysregulation of immune mediated intestinal epithelial healing

免疫介导的肠上皮愈合的脂质失调

基本信息

批准号：
9976797
负责人：
Andrea Alyssa McAlester
金额：
$ 15.39万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/9976797
关键词：
Animals Anti-Inflammatory Agents Apoptotic Atherosclerosis Autoimmune Process Biological Assay CD36 gene Cardiovascular Diseases Cell physiology Cells Chronic Chronic Obstructive Airway Disease Clinical Colitis Data Defect Development Diet Dietary Component Dietary Fats Disease Environment Environmental Risk Factor Epithelial 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 Lead Link Lipids Lupus Mediating Microbe Molecular Mus Pathogenesis Pathology Pathway interactions Penetration Phase Physiology Predisposition Process Production Proteins Receptor Activation Regulation Resolution Role Severities Signal Pathway Signal Transduction Stimulus Support System Symptoms System Testing Tight Junctions Time Tissues chronic inflammatory disease cytokine effective therapy feeding food consumption gut microbiota healing immune function in vivo inflammatory disease of the intestine insight interest intestinal barrier intestinal epithelium intestinal homeostasis intestinal injury macrophage microbial mouse model neutrophil novel pathogen prevent receptor repaired response therapeutic target tissue injury tissue repair tissue-repair responses uptake wound healing

项目摘要

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