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.

项目摘要/摘要 全身性慢性炎症（SCI）是2型糖尿病（T2D）和 炎症性肠病（IBD），例如，它影响25-40％的IBD患者，有助于 IBD的遗外表现。餐后炎症对SCI的贡献 这些环境尚不清楚。我们在T2D患者中的初步数据表明透明质酸（HA） 与血浆炎症细胞因子相关，餐后HA在T2D中高得多 患者可以通过减肥手术快速标准化。我们为餐后建模 饮食引起的肥胖动物模型中的HA尖峰，我们发现这种现象更多 在IBD鼠标模型中发音。使用新的Has2过表达鼠标模型我们 在最近研究脂肪组织HA的出版物中产生的，我们发现循环ha可以 用胶原式结构（MARCO）诱导肝巨噬细胞受体。马可 属于A类寻宝接收器。马可本身没有能力引起创新， 但是可能与细胞内模式识别受体起作用，以刺激炎症 回复。使用新的鼠标模型删除Marco或过表达Marco，我们显示了 增强餐后炎症反应，需要核苷酸结合 在此过程中包含1（nod1）的寡聚域。基于这些数据，我们 假设餐会诱导HA从肠道中快速移动，进入 圆圈以诱导肝巨噬细胞 - 库普弗细胞（KCS）上的Marco表达。饱和 饮食中的脂肪酸使用marco被输送到细胞中以激活NOD1以引起 炎症反应。使用几种基因工程的鼠标模型，我们将检查 （一个）。 HA促进Marco表达在KC中的机制； （b）肝脏的作用 巨噬细胞马可在细胞因子分泌中； （c）炎症刺激的来源和直接 KCS炎症反应的效应因子在三个特定目标中。 AIM 1将决定HA的作用 在餐后肝KC Marco表达中； AIM 2将通过 KC Marco增强了餐后注射并有助于SCI； AIM 3将 评估消化HA还是中和Marco减轻SCI和相关的病理。 完成拟议的研究将提供有关HA-MARCO的新科学知识 餐后创新和SCI中的轴。这些知识将支持控制的想法 循环HA并中和Marco打击SCI和相关疾病。