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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.

摘要 ALD进展的一个关键阶段是肝脏炎症的发展，它实质上增加了患纤维化、肝硬变和癌症的风险。尽管最近免疫调节生物制品的使用激增，但对于其他炎症性疾病，皮质类固醇仍然是治疗肝脏炎症的唯一药物，强调一个主要的未得到满足的临床需求。而有证据表明，乙醇诱导的肝细胞死亡和循环内毒素升高推动ALD的肝脏炎症，一个主要问题是如何慢性低度炎症在ALD的发展过程中被启动和放大。我们报告说，低剂量内毒素诱导作为传感器的C型凝集素受体家族成员Mincle的表达对于细胞死亡，通过肝巨噬细胞中依赖IRAKM的TLR4信号。Mincle检测组件由死亡的肝细胞释放，激活炎症体和IL-1β的产生，是一个关键的环节 ALD小鼠模型中细胞死亡和炎症之间的关系。最近，我们发现血清中的β浓度- 葡萄糖神经酰胺(GluCer)，一种由濒死的肝细胞释放的Mincle配体，通过乙醇喂养增加在小鼠和急性肝炎患者的血清中高度升高。GluCer浓度与患者的疾病严重程度，提示GluCer可能是推动肝脏炎症的主要Mincle配体 ALD中的肝纤维化。有趣的是，Mincle的激活导致肝脏分泌非溶解形式的IL-1β 巨噬细胞和肝星状细胞(HSCs)通过一种新的GSDMD介导的生物发生和释放细胞外小泡(SEV)。非裂解性IL-1β的分泌使肝巨噬细胞免于发生下垂，使他们能够继续放大炎症反应。重要的是，我们的初步数据突出了 IL-1β在增强小鼠酒精性肝损伤中的致病作用。从机制上讲，我们发现IL-1β可诱导肝细胞中saa的表达，进而激活 Caspase3-GSDME介导的下垂。肝细胞下垂释放危险信号HMGB1，它可以进一步激活依赖于caspase 1和11的GSDMD在邻近肝细胞中的裂解，放大肝细胞损伤。这种损伤的升级不仅损害了肝功能，而且可能导致进一步的释放 GluCer，放大巨噬细胞炎症反应。重要的是，我们的初步数据显示，GluCer 还能激活HSCs，促进胶原沉积，加重肝纤维化。通过解剖GluCer- Mincle-GSDMD-IL-1β-SEV级联，这项应用将评估策略并确定治疗靶点阻断这种将早期肝细胞死亡放大为衰弱状态的正反馈环路肝脏炎症和纤维化。