Postprandial activation of hyaluronan-MARCO axis contributes to systemic chronic inflammation

餐后透明质酸-MARCO轴的激活导致全身慢性炎症

• 批准号: 10712757
• 负责人: Yi Zhu
• 金额: $ 43.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712757
• 关键词: Acute; Adipose tissue; Affect; Animal Model; Binding; Blood; CD44 Antigens; CD44 gene; Cells; Cessation of life; Chronic; Chronic Disease; Circulation; Data; Development; Diet; Dietary Component; Digestion; Disease; Dose; Eating; Endocrine system; Endotoxemia; Genetically Engineered Mouse; HAS2 gene; Hepatic; Human; Hyaluronan; Hyperglycemia; Hyperlipidemia; Immune system; Impairment; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Ingestion; Intestines; Knock-out; Knockout Mice; Knowledge; Kupffer Cells; Leukocytes; Link; Liver; Macrophage; Modeling; Modernization; Molecular; Molecular Weight; Movement; Mus; Nervous System; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Organ; Pathology; Patients; Pattern; Pattern recognition receptor; Physiological; Plasma; Process; Production; Publications; RNA Interference; Reproductive system; Research; Role; SR-A proteins; Saturated Fatty Acids; Serum; Sodium Dextran Sulfate; Source; Sperm Adhesion Molecule 1; Stimulus; Structure; Surveys; Testing; Tissues; bariatric surgery; combat; comorbidity; cytokine; diet-induced obesity; gastrointestinal; gut inflammation; gut microbiota; human subject; immune activation; knock-down; liver inflammation; monocyte; mouse model; novel; overexpression; pathogen; receptor; response; systemic inflammatory response; temporal measurement

PROJECT SUMMARY/ABSTRACT Systemic chronic inflammation (SCI) is a common comorbidity of type 2 diabetes (T2D) and inflammatory bowel disease (IBD), e.g., it affects 25-40% of IBD patients, contributing to extraintestinal manifestations of IBD. The contribution of postprandial inflammation to the SCI in those contexts remains unclear. Our preliminary data in T2D patients suggest hyaluronan (HA) correlates with plasma inflammatory cytokines, and postprandial HA is much higher in T2D patients, which can be quickly normalized by bariatric surgery. We modeled this postprandial HA spike in diet-induced obese animal models, and we found this phenomenon was more pronounced in IBD mouse models. With a new Has2 overexpression mouse model we generated in a recent publication studying adipose tissue HA, we found circulating HA can induce hepatic macrophage receptor with collagenous structure (Marco) expression. MARCO belongs to class A scavenger receptors. MARCO itself is not capable of eliciting inflammation, but may function with intracellular pattern recognition receptors to stimulate an inflammatory response. With new mouse models to either delete Marco or overexpress Marco, we showed it augmented postprandial inflammatory response, and required nucleotide-binding oligomerization domain containing 1 (NOD1) in this process. Based on these data, we hypothesize that meal induces quick displacement of HA from the intestinal tract, entering the circulation to induce Marco expression on liver macrophage – Kupffer cells (KCs). Saturated fatty acids from the diet use MARCO to be delivered into the cell to activate NOD1 to elicit an inflammatory response. With several genetically engineered mouse models, we will examine (A). the mechanism by which HA promotes Marco expression in KCs; (B) the role of liver macrophage Marco in cytokine secretion; (C) the source of inflammatory stimuli and the direct effector of KCs inflammatory response in three specific aims. Aim 1 will determine the role of HA in postprandial hepatic KC Marco expression; Aim 2 will determine the molecular mechanism by which KC MARCO enhances postprandial inflammation and contributes to SCI; and Aim 3 will evaluate whether digesting HA or neutralizing MARCO alleviates SCI and related pathologies. Completing the proposed research will provide novel scientific knowledge on the HA-MARCO axis in postprandial inflammation and SCI. This knowledge will support the idea of controlling circulating HA and neutralizing MARCO to combat SCI and related diseases.

项目总结/摘要 全身性慢性炎症（SCI）是2型糖尿病（T2D）的常见合并症， 炎症性肠病（IBD），例如，它影响25 - 40%的IBD患者， IBD的肠外表现。餐后炎症对脊髓损伤的影响 这些背景仍不清楚。我们在T2D患者中的初步数据表明透明质酸（HA） 与血浆炎性细胞因子相关，T2D患者的餐后HA更高 患者，可以通过减肥手术迅速恢复正常。我们模拟了餐后 在饮食诱导的肥胖动物模型中，我们发现这种现象更多的是 在IBD小鼠模型中显著。利用新的Has2过表达小鼠模型， 在最近发表的一篇研究脂肪组织HA的文章中，我们发现循环中的HA可以 诱导具有胶原结构肝巨噬细胞受体（Marco）表达。Marco 属于A类清道夫受体。MARCO本身不能引起炎症， 但可能与细胞内模式识别受体一起起作用， 反应用新的小鼠模型来删除Marco或过度表达Marco， 餐后炎症反应增强，需要核苷酸结合 寡聚化结构域包含1（NOD1）在这个过程中。根据这些数据，我们 假设膳食诱导HA从肠道快速移位，进入 循环以诱导肝脏巨噬细胞-枯否细胞（KCs）上的Marco表达。饱和 饮食中的脂肪酸利用MARCO进入细胞，激活NOD 1， 炎症反应。通过几种基因工程小鼠模型，我们将研究 （一）. HA促进KC中Marco表达的机制;（B）肝脏的作用 巨噬细胞在细胞因子分泌中的作用;（C）炎症刺激的来源和直接 KCs炎症反应的三个具体目标的效应。目标1将决定医管局的角色 在餐后肝脏KC Marco表达中; Aim 2将通过以下方法确定分子机制： KC MARCO增强餐后炎症并导致SCI; Aim 3将 评估消化HA或中和MARCO是否会加重SCI和相关病理。 完成拟议的研究将为HA-MARCO提供新的科学知识 轴在餐后炎症和SCI。这些知识将支持控制的想法， 循环HA和中和MARCO以对抗SCI和相关疾病。