scholarly journals M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Li Bai ◽  
Ming Kong ◽  
Zhongping Duan ◽  
Shuang Liu ◽  
Sujun Zheng ◽  
...  
Keyword(s):  
Liver Failure ◽  
Macrophage Activation ◽  
Chronic Liver ◽  
Inflammasome Activation ◽  
M2 Macrophage ◽  
Chronic Liver Failure ◽  
Lps Challenge ◽  
S100a9 Expression

AbstractNecroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis.

scholarly journals Protective Effects of Taraxacum officinale L. (Dandelion) Root Extract in Experimental Acute on Chronic Liver Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 504
Author(s):  
Iulia Olimpia Pfingstgraf ◽  
Marian Taulescu ◽  
Raluca Maria Pop ◽  
Remus Orăsan ◽  
Laurian Vlase ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Failure ◽  
Tissue Injury ◽  
Taraxacum Officinale ◽  
Chronic Liver ◽  
Root Extract ◽  
Protective Effects ◽  
Stress Tests ◽  
Chronic Liver Failure

Background: Taraxacum officinale (TO) or dandelion has been frequently used to prevent or treat different liver diseases because of its rich composition in phytochemicals with demonstrated effect against hepatic injuries. This study aimed to investigate the possible preventing effect of ethanolic TO root extract (TOERE) on a rat experimental acute on chronic liver failure (ACLF) model. Methods: Chronic liver failure (CLF) was induced by human serum albumin, and ACLF was induced in CLF by D-galactosamine and lipopolysaccharide (D-Gal-LPS). Five groups (n = 5) of male Wistar rats (200–250 g) were used: ACLF, ACLF-silymarin (200 mg/kg b.w./day), three ACLF-TO administered in three doses (200 mg, 100 mg, 50 mg/kg b.w./day). Results: The in vivo results showed that treatment with TOERE administered in three chosen doses before ACLF induction reduced serum liver injury markers (AST, ALT, ALP, GGT, total bilirubin), renal tests (creatinine, urea), and oxidative stress tests (TOS, OSI, MDA, NO, 3NT). Histopathologically, TOERE diminished the level of liver tissue injury and 3NT immunoexpression. Conclusions: This paper indicated oxidative stress reduction as possible mechanisms for the hepatoprotective effect of TOERE in ACLF and provided evidence for the preventive treatment.

scholarly journals Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Gut ◽  
2018 ◽  
Vol 68 (10) ◽  
pp. 1872-1883 ◽  
Author(s):  
Hannelie Korf ◽  
Johannie du Plessis ◽  
Jos van Pelt ◽  
Sofie De Groote ◽  
David Cassiman ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
Liver Failure ◽  
Bacterial Infections ◽  
Chronic Liver ◽  
Decompensated Cirrhosis ◽  
Chronic Liver Failure ◽  
Phenotypic Characterisation ◽  
Severity Scores ◽  
Aclf Patient

ObjectiveAcute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.DesignFollowing phenotypic characterisation, we performed RNA sequencing on CD14+CD16− monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.ResultsMonocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16− monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.ConclusionIn ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.

scholarly journals Hepatoprotective Effect of Yiqijianpi Formula (YQJPF) on Liver Failure Through Modulation of Hypoxic and Apoptosis Pathways

2020 ◽  
Author(s):  
Li Tang ◽  
Feixia Wang ◽  
Lingyan Xiao ◽  
Min Shen ◽  
Siwei Xia ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Signaling Pathways ◽  
Tunel Assay ◽  
Chronic Liver ◽  
Active Components ◽  
Chronic Liver Failure ◽  
Apoptosis Pathway ◽  
L02 Cells

Abstract BackgroundAcute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis, which seriously endanger human life and health. Yiqijianpi decoction (YQJPF) is a Traditional Chinese Medicine (TCM) formula that has been widely used in the treatment of liver failure with significant effect. The purpose of this study was to investigate the active components and mechanism to ameliorate acute on chronic liver failure(ACLF).MethodsLPS combined with D-Gal was used to establish the rat model of ACLF, pathological examination was detected by H&E staining, liver function test was assayed by ELISA. LPS was used to induce hepatocytes injury in vitro. Cell proliferation assay, TUNEL assay were used in human hepatic L02 cells. The active components and putative targets of YQJPF were predicted by network pharmacology approach and GEO analysis. Functional and pathway enrichment analysis were presented by using String, Cytoscape and Metascape. Further, experimental validation was done to verify the effect of YQJPF on PI3K/AKT-HIF-1ɑ and apoptosis-related signaling pathways by using Immunohistochemistry and Western blotting.ResultsAfter being treated with YQJPF, the rat liver injury and fibrosis were alleviated, and Cell Counting Kit-8 assay, TUNEL assay indicated YQJPF also inhibited the apoptosis in hepatic L02 cells. Through network pharmacologic analysis, 135 active components in YQJPF decoction, 573 known therapeutic targets and 2940 liver failure-related human genes were identified. 163 gene symbols maybe the key for liver failure treatment by YQJPF decoction. VEGF-A was hub gene in PPI network. The KEGG pathway and GO enrichment analyses indicated that the PI3K/AKT, HIF-1 signaling pathways were the prominently enriched signaling pathways. In vivo, YQJPF upregulated the expression of PI3K/AKT-HIF1-ɑ and VEGF-A. Moreover apoptosis pathway were verified by up-regulating Bcl2 expression and down-regulating Bax expression in vivo and in vitro.ConclusionYQJPF is beneficial for alleviating liver failure, may regulate hypoxic liver injury through PI3K/AKT-HIF1α dependent apoptosis pathway.

Effects of Plasma from Acute-on-Chronic Liver Failure Patients on Immortalized Human Hepatocytes in vitro

2011 ◽  
Vol 58 (109) ◽  
pp. 1328-1333 ◽  
Author(s):  
Lv Guoliang ◽  
Zhang Anye ◽  
Zhao Lifu ◽  
Pan Xiaoping ◽  
Zhang Yimin ◽  
...  
Keyword(s):  
Liver Failure ◽  
Human Hepatocytes ◽  
Chronic Liver ◽  
Chronic Liver Failure

scholarly journals Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

Gut ◽  
2020 ◽  
pp. gutjnl-2019-320170 ◽  
Author(s):  
Sofia Monteiro ◽  
Josephine Grandt ◽  
Frank Erhard Uschner ◽  
Nina Kimer ◽  
Jan Lysgård Madsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Failure ◽  
Chronic Liver ◽  
Inflammasome Activation ◽  
Chronic Liver Failure ◽  
Experimental Cirrhosis ◽  
Detection Rates ◽  
Compensated Cirrhosis ◽  
Duct Ligation ◽  
European Foundation

ObjectiveSystemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.

Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF)

2016 ◽  
Vol 64 (4) ◽  
pp. 813-822 ◽  
Author(s):  
Henning Grønbæk ◽  
Sidsel Rødgaard-Hansen ◽  
Niels Kristian Aagaard ◽  
Vicente Arroyo ◽  
Søren K. Moestrup ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Failure ◽  
Macrophage Activation ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Activation Markers
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