IRAKM and MINCLE in ALD
ALD 中的 IRAKM 和 MINCLE
基本信息
- 批准号:10750123
- 负责人:
- 金额:$ 60.22万
- 依托单位:
- 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:
- 关键词:AcuteAdrenal Cortex HormonesAffectAlcohol abuseAlcoholic HepatitisAlcoholic Liver DiseasesAlcoholsAmericanAnimal ModelAutomobile DrivingBinding ProteinsBiogenesisBiological Response ModifiersC Type Lectin ReceptorsCASP1 geneCarbon TetrachlorideCaspaseCell DeathChronicCirrhosisClinicalCollagenComplexDataDepositionDevelopmentDiseaseDisease ProgressionDoseEndotoxinsEthanolFamilyFibrosisFoundationsFutureGenesGlucosylceramidesHMGB1 geneHepaticHepatic Stellate CellHepatitisHepatocyteIL18 geneIRAK3 geneIRAK4 geneImpairmentInflammasomeInflammationInflammatoryInflammatory ResponseInjuryInnate Immune ResponseInterleukin-1Interleukin-1 betaInterruptionInterventionIntestinal permeabilityKupffer CellsLeadLigandsLinkLipid BindingLipopolysaccharidesLiverLiver FibrosisLiver diseasesMacrophageMalignant NeoplasmsMediatingModelingMolecularMorbidity - disease rateMusNonlyticPathogenesisPathogenicityPathway interactionsPatientsPeripheral Blood Mononuclear CellPlayPrimary carcinoma of the liver cellsProductionProteinsReportingRiskRoleSerumSerum amyloid A proteinSeverity of illnessSignal TransductionSpliceosomesTLR4 geneTNF geneTestingTherapeuticTherapeutic Interventioncell injurycytokineeffective therapyend stage liver diseaseextracellular vesiclesfeedingfibrogenesishepatocellular injuryhepatocyte injuryliver functionliver inflammationliver injurymembermicrobiotamortalitymouse modelnovelnovel therapeutic interventionpharmacologicprogramsrational designresponsesensorstellate celltherapeutic targettreatment 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LAURA E. NAGY其他文献
LAURA E. NAGY的其他文献
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{{ truncateString('LAURA E. NAGY', 18)}}的其他基金
Transcriptional and non-transcriptional functions of IRF3 in ALD
IRF3 在 ALD 中的转录和非转录功能
- 批准号:
10207370 - 财政年份:2019
- 资助金额:
$ 60.22万 - 项目类别:
Transcriptional and non-transcriptional functions of IRF3 in ALD
IRF3 在 ALD 中的转录和非转录功能
- 批准号:
10430300 - 财政年份:2019
- 资助金额:
$ 60.22万 - 项目类别:
Transcriptional and non-transcriptional functions of IRF3 in ALD
IRF3 在 ALD 中的转录和非转录功能
- 批准号:
10173028 - 财政年份:2019
- 资助金额:
$ 60.22万 - 项目类别:
Transcriptional and non-transcriptional functions of IRF3 in ALD
IRF3 在 ALD 中的转录和非转录功能
- 批准号:
9765602 - 财政年份:2019
- 资助金额:
$ 60.22万 - 项目类别:
Microbial metabolites and Innate Immunity in AH: Biomarkers of injury and repair
AH 中的微生物代谢物和先天免疫:损伤和修复的生物标志物
- 批准号:
10428502 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:
Specific-sized hyaluronan: a dual targeted therapy for ALD
特定大小的透明质酸:ALD 的双重靶向治疗
- 批准号:
10227144 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:
Specific-sized hyaluronan: a dual targeted therapy for ALD
特定大小的透明质酸:ALD 的双重靶向治疗
- 批准号:
9753072 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:
Specific-sized hyaluronan: a dual targeted therapy for ALD
特定大小的透明质酸:ALD 的双重靶向治疗
- 批准号:
10457954 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:
Microbial metabolites and Innate Immunity in AH: Biomarkers of injury and repair
AH 中的微生物代谢物和先天免疫:损伤和修复的生物标志物
- 批准号:
9791131 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:
Specific-sized hyaluronan: a dual targeted therapy for ALD
特定大小的透明质酸:ALD 的双重靶向治疗
- 批准号:
9977058 - 财政年份:2018
- 资助金额:
$ 60.22万 - 项目类别:














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