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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