The Role of NLRP3 Inflammasome Activation Pathway of Hepatic Macrophages in Liver Ischemia–Reperfusion Injury

Wu, Tong; Zhang, Cheng; Shao, Tianfeng; Chen, Jianzhong; Chen, Diyu

doi:10.3389/fimmu.2022.905423

Cited by 6 publications

(4 citation statements)

References 69 publications

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“… 31 NLPR3 is highly expressed in hepatic macrophages, and NLRP3 inflammasome activation plays an important role in promoting inflammatory liver IR injury. 32 We have previously found that aging aggravates liver IR injury by promoting macrophage NLRP3 activation. 8 19 A recent study also found that NLRP3 mediates the inflammatory response and pyroptosis in macrophages during fatty liver IR injury.…”

Section: Discussionmentioning

confidence: 96%

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Li,

Guan,

Gao

et al. 2024

Hepatology Communications

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Background: Fatty livers are widely accepted as marginal donors for liver transplantation but are more susceptible to liver ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty liver IR injury. Here, we investigate the precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain–associated protein 3 (NLRP3) signaling by regulating mitochondrial calcium overload in fatty liver IR. Methods: Control- and high-fat diet-fed mice were subjected to a partial liver IR model. The ER stress, mitochondrial calcium levels, and NLRP3 signaling pathway in macrophages were analyzed. Results: Liver steatosis exacerbated liver inflammation and IR injury and enhanced NLRP3 activation in macrophages. Myeloid NLRP3 deficiency attenuated intrahepatic inflammation and fatty liver injury following IR. Mechanistically, increased ER stress and mitochondrial calcium overload were observed in macrophages obtained from mouse fatty livers after IR. Suppression of ER stress by tauroursodeoxycholic acid effectively downregulated mitochondrial calcium accumulation and suppressed NLRP3 activation in macrophages, leading to decreased inflammatory IR injury in fatty livers. Moreover, Xestospongin-C–mediated inhibition of mitochondrial calcium influx decreased reactive oxygen species (ROS) expression in macrophages after IR. Scavenging of mitochondrial ROS by mito-TEMPO suppressed macrophage NLRP3 activation and IR injury in fatty livers, indicating that excessive mitochondrial ROS production was responsible for macrophage NLRP3 activation induced by mitochondrial calcium overload. Patients with fatty liver also exhibited upregulated activation of NLRP3 and the ER stress signaling pathway after IR. Conclusions: Our findings suggest that ER stress promotes mitochondrial calcium overload to activate ROS/NLRP3 signaling pathways within macrophages during IR-stimulated inflammatory responses associated with fatty livers.

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Section: Discussionmentioning

confidence: 96%

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Li,

Guan,

Gao

et al. 2024

Hepatology Communications

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“…The sterile inflammatory response of HIRI was diven by innate immunity initiated by recognizing pattern-recognition receptors (PRRs), including NLRP3 ( 2 , 24 , 25 ). NLRP3 has been identified as a major contributor to liver injury and amplification of liver inflammation, making it a promising therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning

Xiao,

Huang,

Yuan

et al. 2024

Front. Immunol.

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Background and aimsCuproptosis has emerged as a significant contributor in the progression of various diseases. This study aimed to assess the potential impact of cuproptosis-related genes (CRGs) on the development of hepatic ischemia and reperfusion injury (HIRI).MethodsThe datasets related to HIRI were sourced from the Gene Expression Omnibus database. The comparative analysis of differential gene expression involving CRGs was performed between HIRI and normal liver samples. Correlation analysis, function enrichment analyses, and protein-protein interactions were employed to understand the interactions and roles of these genes. Machine learning techniques were used to identify hub genes. Additionally, differences in immune cell infiltration between HIRI patients and controls were analyzed. Quantitative real-time PCR and western blotting were used to verify the expression of the hub genes.ResultsSeventy-five HIRI and 80 control samples from three databases were included in the bioinformatics analysis. Three hub CRGs (NLRP3, ATP7B and NFE2L2) were identified using three machine learning models. Diagnostic accuracy was assessed using a receiver operating characteristic (ROC) curve for the hub genes, which yielded an area under the ROC curve (AUC) of 0.832. Remarkably, in the validation datasets GSE15480 and GSE228782, the three hub genes had AUC reached 0.904. Additional analyses, including nomograms, decision curves, and calibration curves, supported their predictive power for diagnosis. Enrichment analyses indicated the involvement of these genes in multiple pathways associated with HIRI progression. Comparative assessments using CIBERSORT and gene set enrichment analysis suggested elevated expression of these hub genes in activated dendritic cells, neutrophils, activated CD4 memory T cells, and activated mast cells in HIRI samples versus controls. A ceRNA network underscored a complex regulatory interplay among genes. The genes mRNA and protein levels were also verified in HIRI-affected mouse liver tissues.ConclusionOur findings have provided a comprehensive understanding of the association between cuproptosis and HIRI, establishing a promising diagnostic pattern and identifying latent therapeutic targets for HIRI treatment. Additionally, our study offers novel insights to delve deeper into the underlying mechanisms of HIRI.

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“…Macrophages have been recognized as the main cells responsible for NLRP3 activation via ROS production during LIRI [70,86]. In fact, the knockdown of NLRP3 in mice leads to a reduction of serum alanine aminotransferase levels and a decreased production of pro-inflammatory cytokines such as IL-1β, IL-18, IL-6, and TNFα, leading to liver protection from ischemia-reperfusion damage [87].…”

Section: Type Of Cld Effect Sex and Species Referencesmentioning

confidence: 99%

NLRP3 Inflammasome in Acute and Chronic Liver Diseases

Sayaf,

Battistella,

Russo

2024

IJMS

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NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. The NLRP3 inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well as IL-18 and IL-1β production. Acute and chronic liver diseases are characterized by a massive influx of pro-inflammatory stimuli enriched in reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that promote the assemblage and activation of the NLRP3 inflammasome. As the major cause of inflammatory cytokine storm, the NLRP3 inflammasome exacerbates liver diseases, even though it might exert protective effects in regards to hepatitis C and B virus infection (HCV and HBV). Here, we summarize the current knowledge concerning NLRP3 inflammasome function in both acute and chronic liver disease and in the post liver transplant setting, focusing on the molecular mechanisms involved in NLRP3 activity.

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The Role of NLRP3 Inflammasome Activation Pathway of Hepatic Macrophages in Liver Ischemia–Reperfusion Injury

Cited by 6 publications

References 69 publications

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning

NLRP3 Inflammasome in Acute and Chronic Liver Diseases

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