IRAKM and MINCLE in ALD

ALD 中的 IRAKM 和 MINCLE

基本信息

批准号：
10750123
负责人：
LAURA E. NAGY
金额：
$ 60.22万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750123
关键词：
Acute Adrenal Cortex Hormones Affect Alcohol abuse Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols American Animal Model Automobile Driving Binding Proteins Biogenesis Biological Response Modifiers C Type Lectin Receptors CASP1 gene Carbon Tetrachloride Caspase Cell Death Chronic Cirrhosis Clinical Collagen Complex Data Deposition Development Disease Disease Progression Dose Endotoxins Ethanol Family Fibrosis Foundations Future Genes Glucosylceramides HMGB1 gene Hepatic Hepatic Stellate Cell Hepatitis Hepatocyte IL18 gene IRAK3 gene IRAK4 gene Impairment Inflammasome Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Interleukin-1 Interleukin-1 beta Interruption Intervention Intestinal permeability Kupffer Cells Lead Ligands Link Lipid Binding Lipopolysaccharides Liver Liver Fibrosis Liver diseases Macrophage Malignant Neoplasms Mediating Modeling Molecular Morbidity - disease rate Mus Nonlytic Pathogenesis Pathogenicity Pathway interactions Patients Peripheral Blood Mononuclear Cell Play Primary carcinoma of the liver cells Production Proteins Reporting Risk Role Serum Serum amyloid A protein Severity of illness Signal Transduction Spliceosomes TLR4 gene TNF gene Testing Therapeutic Therapeutic Intervention cell injury cytokine effective therapy end stage liver disease extracellular vesicles feeding fibrogenesis hepatocellular injury hepatocyte injury liver function liver inflammation liver injury member microbiota mortality mouse model novel novel therapeutic intervention pharmacologic programs rational design response sensor stellate cell therapeutic target treatment strategy

项目摘要

ABSTRACT A pivotal stage of the ALD progression is the development of hepatic inflammation, which substantially increases the risk for fibrosis, cirrhosis and cancer. Despite the recent surge in the use of immunomodulatory biologics for other inflammatory diseases, corticosteroids remain the only therapeutic for hepatic inflammation, underscoring a major unmet clinical need. While evidence indicates that a combination of ethanol-induced hepatocyte cell death and elevated circulating endotoxin drives hepatic inflammation in ALD, a major question arising is how the chronic low grade inflammation is initiated and amplified in the progression of ALD. We reported that low-dose endotoxin induces the expression of Mincle, a member of the C-type lectin receptor family that acts as a sensor for cell death, via the IRAKM-dependent TLR4 signaling in hepatic macrophages. Mincle detects components released by dead hepatocytes and activates inflammasomes and IL-1β production, serving as a critical link between cell death and inflammation in murine models of ALD. Recently, we found serum concentrations of β- glucosylceramide (GluCer), a Mincle ligand released by dying hepatocytes, are increased by ethanol feeding in mice and highly elevated in sera from patients with AH. GluCer concentrations were positively correlated with disease severity in patients, suggesting that GluCer may be a major Mincle ligand driving hepatic inflammation and fibrosis in ALD. Intriguingly, Mincle activation leads to a non-lytic form of IL-1β secretion from hepatic macrophages and hepatic stellate cells (HSCs) via a novel GSDMD-mediated biogenesis and release of small extracellular vesicles (sEVs). The non-lytic IL-1β secretion spares hepatic macrophages from pyroptosis, allowing them to continue amplifying the inflammatory response. Importantly, our preliminary data highlight a critical pathogenic role for IL-1β containing sEVs in potentiating ethanol-induced liver injury in mice. Mechanistically, we found that IL-1β induced the expression of SAA in hepatocytes, which in turn activated caspase3-GSDME-mediated pyroptosis. Hepatocyte pyroptosis releases the danger signal HMGB1, which can further activate caspase 1 and 11-dependent GSDMD-cleavage in neighboring hepatocytes, amplifying hepatocyte injury. This escalation of injury not only impairs liver function but likely leads to further release of GluCer, amplifying macrophage inflammatory responses. Importantly, our preliminary data reveal that GluCer also activated HSCs, enhancing collagen deposition and aggravating liver fibrosis. By dissecting the GluCer- Mincle-GSDMD-IL-1β-sEV cascade, this application will evaluate strategies and identify therapeutic targets to interrupt this positive feed forward loop that amplifies the early stage hepatocyte cell death into debilitating hepatic inflammation and fibrosis.

抽象的 ALD进展的关键阶段是肝炎感染的发展，其次增加纤维化，肝硬化和癌症的风险。尽管最近使用免疫调节生物制剂激增其他炎症性疾病，皮质类固醇仍然是肝注射的唯一治疗性，强调主要未满足的临床需求。虽然证据表明乙醇诱导的肝细胞的组合死亡和循环内毒素升高驱动ALD的肝炎注射，引起的一个主要问题是如何在ALD的进展中启动并扩大了慢性低年级炎症。我们报告了低剂量内毒素诱导Mincle的表达，Mincle是C型讲座受体家族的成员，充当传感器对于细胞死亡，通过肝巨噬细胞中的IRAKM依赖性TLR4信号传导。 Mincle检测组件由死亡的肝细胞发行并激活感染和IL-1β产生，作为关键联系在ALD的鼠模型中细胞死亡和炎症之间。最近，我们发现β-的血清浓度葡萄糖基酰胺（Glucer）是通过垂死的肝细胞释放的微小配体，通过乙醇进食来增加 AH患者血清中的小鼠和高度升高。引导者浓度与患者的疾病严重程度，表明Glucer可能是驱动肝脏注射的主要大小配体和ALD中的纤维化。有趣的是，Mincle激活导致肝的非晶状形式的IL-1β分泌巨噬细胞和肝星状细胞（HSC）通过新型的GSDMD介导的生物发生和小的释放细胞外蔬菜（SEV）。非悠久的IL-1β分泌释放了来自pyrptosis的肝巨噬细胞，允许他们继续扩大炎症反应。重要的是，我们的初步数据突出显示在潜在乙醇诱导的小鼠肝损伤中含有IL-1β的关键致病作用。从机械上讲，我们发现IL-1β诱导了肝细胞中SAA的表达，进而激活 caspase3-GSDME介导的凋亡。肝细胞凋亡释放危险信号HMGB1，可以进一步激活caspase 1和11依赖性的GSDMD - 切 - 相邻肝细胞中的裂解，放大肝细胞损伤。伤害的升级不仅会损害肝功能，而且可能导致进一步释放 glucer，扩增巨噬细胞炎症反应。重要的是，我们的初步数据表明了葡萄糖还激活了HSC，增强胶原蛋白沉积并加剧肝纤维化。通过剖析葡萄糖 Mincle-GSDMD-IL-1β-SEV级联，此应用将评估策略并确定治疗目标打断这种积极的饲料向前循环，该循环在早期肝细胞细胞死亡中放大肝炎和纤维化。