scholarly journals Dual role of neutrophils in modulating liver injury and fibrosis during development and resolution of diet-induced murine steatohepatitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrea D. Kim ◽  
Sung Eun Kim ◽  
Aleksandra Leszczynska ◽  
Benedikt Kaufmann ◽  
Agustina Reca ◽  
...  
Keyword(s):  
Liver Injury ◽  
Control Diet ◽  
Protective Effects ◽  
Alcoholic Fatty Liver ◽  
Complex Locus ◽  
Neutrophil Depletion ◽  
Inflammation Resolution ◽  
Inflammatory Macrophages ◽  
Inflammatory Changes

AbstractInflammatory changes in the liver represent a key feature of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD). Innate immune activation including hepatic neutrophilic infiltration acts as an important inflammatory trigger as well as a potential mediator of inflammation resolution. In this study, we dissected the effects of neutrophil depletion via anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibodies administration during ongoing high fat-fructose-cholesterol (FFC) diet-induced murine NASH and during inflammation resolution by switching into a low-fat control diet. During NASH progression, protective effects were shown as HSC activation, cell infiltration and activation of pro-inflammatory macrophages were ameliorated. Furthermore, these changes were contrasted with the effects observed when neutrophil depletion was performed during the resolution phase. Impaired resolving mechanisms, such as a failure to balance the pro and anti-inflammatory cytokines ratio, deficient macrophage phenotypic switch into a pro-restorative profile, and defective repair and remodeling processes were observed when neutrophils were depleted in this scenario. This study described phase-dependent contrasting roles of neutrophils as triggers and pro-resolutive mediators of liver injury and fibrosis associated with diet-induced NASH in mice. These findings have important translational implications at the time of designing NASH therapeutic strategies.

scholarly journals Caveolin-1 Deficiency Protects Mice Against Carbon Tetrachloride-Induced Acute Liver Injury Through Regulating Polarization of Hepatic Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziheng Yang ◽  
Jie Zhang ◽  
Yan Wang ◽  
Jing Lu ◽  
Quan Sun
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Liver Diseases ◽  
Acute Liver Injury ◽  
Mrna Levels ◽  
Alcoholic Fatty Liver ◽  
Caveolin 1 ◽  
Hepatic Macrophages ◽  
M1 Phenotype

Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury.

scholarly journals Role of Fn14 in acute alcoholic steatohepatitis in mice

2015 ◽  
Vol 308 (4) ◽  
pp. G325-G334 ◽  
Author(s):  
Gamze Karaca ◽  
Guanhua Xie ◽  
Cynthia Moylan ◽  
Marzena Swiderska-Syn ◽  
Cynthia D. Guy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Injury ◽  
Control Diet ◽  
Alcohol Exposure ◽  
Tnf Receptor ◽  
High Fat ◽  
Alcoholic Steatohepatitis ◽  
Tnf Α ◽  
Induce Liver Injury

TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14+ progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-α expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-α expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-α induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure.

The role of MIF in hepatic function, oxidative stress, and inflammation in thioacetamide-induced liver injury in mice: Protective effects of betaine

2020 ◽  
Vol 27 ◽  
Author(s):  
Dušan Vukićević ◽  
Branislav Rovčanin ◽  
Kristina Gopčević ◽  
Sanja Stanković ◽  
Danijela Vučević ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Total Antioxidant Status ◽  
Hepatic Function ◽  
Protective Effects ◽  
Reactive Protein ◽  
Mediated Effects ◽  
Total Antioxidant ◽  
Oxidant Status

Background: Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that contributes to the inflammatory response to chemical liver injury. This cytokine exhibits pro- and anti-inflammatory effects depending on etiology and stage of liver disease. Objective: Our study aimed to investigate the role of MIF in oxidative stress and the inflammation in the liver, and modulatory effects of betaine on MIF in thioacetamide (TAA)-induced chronic hepatic damage in mice. Methods: The experiment was performed on wild type and knockout MIF-/- C57BL/6 mice. They were divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/-+Bet; TAA-group, received of TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/-+TAA+Bet. In TAA- and Bet-treated groups, animals received in the same previous doses. After eight weeks of treatment, blood samples were collected for biochemical analysis and liver specimens were prepared for assessment the parameters of oxidative stress and inflammation. Results: In MIF-/-mice, TAA reduced transaminases, -glutamyltranspeptidase, bilirubin, malondaldehyde (MDA), oxidative protein products (AOPP), total oxidant status (TOS), C-reactive protein (CRP), IL-6, IFN- , and increased of thiols and total antioxidant status (TAS). Betain attenuates mechanism of MIF-mediated effects in TAA-induced liver injury, reducing transaminases, -glutamyltranspeptidase, bilirubin, MDA, AOPP, TOS, CRP, IL-6, IFN-g and increasing thiols. Conclusion: MIF is mediator in hepatotoxic, pro-oxidative and proinfammatory effects of TAA-induced liver injury. MIFtargeted therapy could potentially mitigate the oxidative stress and inflammation in the liver, but the exact mechanism of its action requires further investigation. Betaine increases antioxidative defense and attenuates hepatotoxic effects of MIF, suggesting that betaine can be used for the prevention and treatment of liver damage.

Abstract P444: Inflammation Resolution And Transition Of Macrophages Are Dependent On Ikke

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hyang Hee Cho ◽  
Yong Sook Kim ◽  
Dong Im Cho ◽  
Meeyoung Cho ◽  
Youngkeun Ahn
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Coronary Artery Ligation ◽  
Wild Type ◽  
Poor Survival ◽  
Artery Ligation ◽  
Inflammatory Phenotype ◽  
Inflammation Resolution ◽  
Inflammatory Macrophages

Rationale: Myocardial infarction (MI) is a major cause of death and inflammation mainly contributes to pathological progress. Expression of IKKe is induced in inflammatory macrophages, but the pathophysiological roles in cardiac injury remain unclear. Objective: We aimed to investigate the role of IKKe in macrophages in the IKKe knockout (KO) MI mouse model. Methods and Results: MI was induced by coronary artery ligation, then cardiac macrophages and bone marrow-derived macrophages were isolated for further comparison studies.The IKKe KO group showed poor survival rate, high circulating IL-6 level, large cardiac fibrosis (14.7±4.8% vs. 31.1±10.2%, p<0.05), and low ejection fraction (34.02±5.5% vs. 30.33±5.3% vs. p<0.05) compared with the wild type (WT) group.Next, we investigated the inflammatory and fibrotic responses to understand the relevant mechanism. Flow cytometry and phosphorylated protein array showed that IKKe-deficient macrophages exhibited lower phosphorylated p38 and higher inflammatory markers.Moreover, we identified macrophage-myofibroblast transition (MMT) by detecting aSMA expression in macrophages, and found that the number of cells under MMT was 2.0-fold higher in the IKKe KO group than in the WT group.In parallel to the increase in MMT, the transition of CD206(+) anti-inflammatory macrophages to myofibroblasts was 2.16-fold greater in the IKKe KO mice.Macrophages with chemical or genetic interfering of p38 displayed the remarkable increases in both MMT and inflammatory phenotype. Conclusions: Our results suggest that IKKe-p38 axis may potentially induce the inflammation resolution and limit MMT in macrophages in response to MI. Mechanistical understanding of IKKe signaling offers novel therapeutic pathways to treat MI.

Role of non-parenchymal liver cells in ischaemia-reperfusion liver injury: protective effects of muramyl dipeptide

1994 ◽  
Vol 7 (s1) ◽  
pp. 139-143 ◽  
Author(s):  
Jean Gugenheim ◽  
Francesco Crafa ◽  
Giovanni Dammerota ◽  
Alberto Evangelista ◽  
Marie-Christine Saint-Paul ◽  
...  
Keyword(s):  
Liver Injury ◽  
Muramyl Dipeptide ◽  
Liver Cells ◽  
Protective Effects ◽  
Ischaemia Reperfusion ◽  
Parenchymal Liver
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