Type 3 innate lymphoid cell: a new player in liver fibrosis progression

2018 ◽  
Vol 132 (24) ◽  
pp. 2565-2582 ◽  
Author(s):  
Siqi Wang ◽  
Jing Li ◽  
Shengdi Wu ◽  
Lisha Cheng ◽  
Yue Shen ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Lymphoid Cell ◽  
Mouse Liver ◽  
Stellate Cell ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Innate Lymphoid Cell ◽  
Fibrosis Progression ◽  
Rag 1 ◽  
Type 3

Type 3 innate lymphoid cell (ILC3) has recently emerged as a crucial effector in inflammatory and fibrotic diseases. The present study was designed to determine the roles of ILC3 in liver fibrosis. By flow cytometry, we documented increased frequencies of peripheral ILC3 (Lin−CD127+CD117+CD294− lymphocytes) in patients, especially at the advanced stage of hepatitis B virus (HBV)-related chronic liver diseases, and demonstrated their correlations with disease progression. The in vitro fibrogenic effects by ILC3 were determined by co-culture experiments with LX-2 (a human hepatic stellate cell (HSC) line). The data indicate that pathogenic ILC3 can directly promote LX-2 fibrogenesis in non-contact manners by producing interleukin (IL)-17A and IL-22. Additionally, they had indirect fibrogenic effects by producing IL-22 to suppress interferon (IFN)-γ (a well-known anti-fibrotic cytokine) production by other immune cells. In carbon tetrachloride (CCl4)-induced wild-type mouse liver fibrosis models, we also documented significantly increased frequencies of both non-natural killer (NK) ILC (Lin−CD127+ lymphocytes) and ILC3 (Lin−CD127+RORγt+ lymphocytes) in liver and spleen specimens. Furthermore, the ILC3 from fibrotic mice contained more IL-17A+ILC3 and IL-22+ILC3 subsets than those from normal and less-fibrotic mice. The in vivo effects of ILC3 in liver fibrogenesis were further determined using RAG-1−/− mice with ILC depletion and further adoptive transfer of ILC3 from wild-type mice. The immunohistochemical staining of liver specimens showed the beneficial effects by ILC depletion and the detrimental effects by ILC3 transfer in CCl4-induced mouse liver fibrosis models. Collectively, ILC3 plays a pro-fibrotic role in liver fibrosis progression.

scholarly journals Identification of GDF15 as A Pro-Fibrotic Factor in Mouse Liver Fibrosis Progression

2021 ◽  
Author(s):  
Peng Qi ◽  
Ming-Ze Ma ◽  
Jing-Hua Kuai
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Cell Activation ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Fibrosis Progression

Abstract Aim:To elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells of mice.Methods:We generated a GDF15-neutralizing antibody that can inhibit TGF-β1-induced activation of the TGF-β/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary hepatic stellate cells from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis in mice were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-β pathway was detected using dual-luciferase reporter assays and Western blotting assays.Results:The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-β pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary hepatic stellate cells. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression.Conclusions:The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-β signalling.

Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis

2019 ◽  
Author(s):  
Ryodai Shindo ◽  
Masaki Ohmuraya ◽  
Sachiko Komazawa-Sakon ◽  
Sanae Miyake ◽  
Soh Yamazaki ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lymphoid Cell ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Innate Lymphoid Cell ◽  
Type 3

scholarly journals Farnesoid X Receptor Antagonizes JNK Signaling Pathway in Liver Carcinogenesis by Activating SOD3

2015 ◽  
Vol 29 (2) ◽  
pp. 322-331 ◽  
Author(s):  
Yan-Dong Wang ◽  
Wei-Dong Chen ◽  
Cunbao Li ◽  
Cong Guo ◽  
Yanyan Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hepg2 Cells ◽  
Mouse Liver ◽  
Wild Type Mouse ◽  
Farnesoid X Receptor ◽  
Ros Production ◽  
Wild Type ◽  
Liver Carcinogenesis ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

Abstract The farnesoid X receptor (FXR) is a key metabolic and homeostatic regulator in the liver. In the present work, we identify a novel role of FXR in antagonizing c-Jun N-terminal kinase (JNK) signaling pathway in liver carcinogenesis by activating superoxide dismutase 3 (SOD3) transcription. Compared with wild-type mouse liver, FXR−/− mouse liver showed elevated JNK phosphorylation. JNK1 deletion suppressed the increase of diethylnitrosamine-induced tumor number in FXR−/− mice. These results suggest that JNK1 plays a key role in chemical-induced liver carcinogenesis in FXR−/− mice. We found that ligand-activated FXR was able to alleviate H2O2 or tetradecanoylphorbol acetate-induced JNK phosphorylation in human hepatoblastoma (HepG2) cells or mouse primary hepatocytes. FXR ligand decreased H2O2-induced reactive oxygen species (ROS) levels in wild-type but not FXR−/− mouse hepatocytes. FXR knockdown abolished the inhibition of 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-Benzoic acid (GW4064) on JNK phosphorylation and ROS production induced by H2O2 in HepG2 cells. The gene expression of SOD3, an antioxidant defense enzyme, was increased by FXR activation in vitro and in vivo. An FXR-responsive element, inverted repeat separated by 1 nucleotide in SOD3 promoter, was identified by a combination of transcriptional reporter assays, EMSAs, and chromatin immunoprecipitation assays, which indicated that SOD3 could be a direct FXR target gene. SOD3 knockdown abolished the inhibition of GW4064 on JNK phosphorylation induced by H2O2 in HepG2 cells. In summary, FXR may regulate SOD3 expression to suppress ROS production, resulting in decreasing JNK activity. These results suggest that FXR, as a novel JNK suppressor, may be an attractive therapeutic target for liver cancer treatment.

scholarly journals Insulin-like Growth Factor 1 Supports a Pulmonary Niche that Promotes Type 3 Innate Lymphoid Cell Development in Newborn Lungs

Immunity ◽  
2020 ◽  
Vol 52 (2) ◽  
pp. 275-294.e9 ◽  
Author(s):  
Katherine Oherle ◽  
Elizabeth Acker ◽  
Madeline Bonfield ◽  
Timothy Wang ◽  
Jerilyn Gray ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lymphoid Cell ◽  
Cell Development ◽  
Insulin Like Growth Factor ◽  
Innate Lymphoid Cell ◽  
Type 3

scholarly journals Innate lymphoid cell type 3–derived interleukin-22 boosts lipocalin-2 production in intestinal epithelial cells via synergy between STAT3 and NF-κB

2019 ◽  
Vol 294 (15) ◽  
pp. 6027-6041 ◽  
Author(s):  
Maarten Coorens ◽  
Anna Rao ◽  
Stefanie Katharina Gräfe ◽  
Daniel Unelius ◽  
Ulrik Lindforss ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lymphoid Cell ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Lipocalin 2 ◽  
Cell Type ◽  
Innate Lymphoid Cell ◽  
Interleukin 22 ◽  
Type 3

scholarly journals Ketogenic Diet Enhances the Cholesterol Accumulation in Liver and Augments the Severity of CCl4 and TAA-Induced Liver Fibrosis in Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 2934
Author(s):  
Yi-Jen Liao ◽  
Yuan-Hsi Wang ◽  
Chien-Ying Wu ◽  
Fang-Yu Hsu ◽  
Chia-Ying Chien ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Ketogenic Diet ◽  
Transforming Growth Factor ◽  
Ketone Bodies ◽  
Stellate Cell ◽  
Metabolic Effects ◽  
High Fat ◽  
Cholesterol Accumulation ◽  
Fibrosis Progression

Persistent chronic liver diseases increase the scar formation and extracellular matrix accumulation that further progress to liver fibrosis and cirrhosis. Nevertheless, there is no antifibrotic therapy to date. The ketogenic diet is composed of high fat, moderate to low-protein, and very low carbohydrate content. It is mainly used in epilepsy and Alzheimer’s disease. However, the effects of the ketogenic diet on liver fibrosis remains unknown. Through ketogenic diet consumption, β-hydroxybutyrate (bHB) and acetoacetate (AcAc) are two ketone bodies that are mainly produced in the liver. It is reported that bHB and AcAc treatment decreases cancer cell proliferation and promotes apoptosis. However, the influence of bHB and AcAc in hepatic stellate cell (HSC) activation and liver fibrosis are still unclear. Therefore, this study aimed to investigate the effect of the ketogenic diet and ketone bodies in affecting liver fibrosis progression. Our study revealed that feeding a high-fat ketogenic diet increased cholesterol accumulation in the liver, which further enhanced the carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. In addition, more severe liver inflammation and the loss of hepatic antioxidant and detoxification ability were also found in ketogenic diet-fed fibrotic mouse groups. However, the treatment with ketone bodies (bHB and AcAc) did not suppress transforming growth factor-β (TGF-β)-induced HSC activation, platelet-derived growth factor (PDGF)-BB-triggered proliferation, and the severity of CCl4-induced liver fibrosis in mice. In conclusion, our study demonstrated that feeding a high-fat ketogenic diet may trigger severe steatohepatitis and thereby promote liver fibrosis progression. Since a different ketogenic diet composition may exert different metabolic effects, more evidence is necessary to clarify the effects of a ketogenic diet on disease treatment.

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