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脏炎症的发展，这会大大增加尽管最近免疫调节生物制剂的使用激增，但仍存在纤维化、肝硬化和癌症的风险。与其他炎症性疾病相比，皮质类固醇仍然是治疗肝脏炎症的唯一疗法，强调一个主要的未满足的临床需求，而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会导致 ALD 中的肝脏炎症，出现的一个主要问题是我们报道低剂量的 ALD 会引发并放大慢性低度炎症。内毒素诱导 Mincle 的表达，Mincle 是 C 型凝集素受体家族的成员，充当传感器 Mincle 通过肝巨噬细胞中的 IRAKM 依赖性 TLR4 信号传导来检测细胞死亡。由死亡肝细胞释放并激活炎症小体和 IL-1β 的产生，是一个关键环节最近，我们发现了 ALD 小鼠模型中细胞死亡和炎症之间的关系。葡萄糖神经酰胺 (GluCer) 是一种由死亡肝细胞释放的 Mincle 配体，通过摄入乙醇而增加小鼠体内的 GluCer 浓度与 AH 患者血清中的高度升高呈正相关。患者疾病严重程度，表明 GluCer 可能是驱动肝脏炎症的主要 Mincle 配体有趣的是，Mincle 激活导致肝脏分泌非裂解形式的 IL-1β。巨噬细胞和肝星状细胞 (HSC) 通过新型 GSDMD 介导的生物发生和小分子释放细胞外囊泡 (sEV) 的非裂解性 IL-1β 分泌使肝巨噬细胞免于焦亡，重要的是，我们的初步数据强调了这一点。含有IL-1β的sEV在增强小鼠乙醇诱导的肝损伤中发挥关键致病作用。从机制上讲，我们发现IL-1β诱导肝细胞中SAA的表达，进而激活 caspase3-GSDME 介导的肝细胞焦亡释放危险信号 HMGB1，该信号可以进一步激活邻近肝细胞中的 caspase 1 和 11 依赖性 GSDMD 裂解，放大肝细胞损伤的加剧不仅损害肝功能，而且可能导致进一步释放。 GluCer，放大巨噬细胞炎症反应重要的是，我们的初步数据表明 GluCer。还通过解剖 GluCer- 激活 HSC，增强胶原蛋白沉积并加剧肝纤维化。 Mincle-GSDMD-IL-1β-sEV 级联，该应用程序将评估策略并确定治疗靶点中断这种将早期肝细胞死亡放大到衰弱的正前馈循环肝脏炎症和纤维化。