Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis

AbstractLiver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1−/− mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.

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Methane-Rich Saline Counteracts Cholestasis-Induced Liver Damage via Regulating the TLR4/NF-κB/NLRP3 Inflammasome Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6565283 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Zeyu Li ◽

Dongdong Chen ◽

Yifan Jia ◽

Yang Feng ◽

Cong Wang ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Inflammatory Cells ◽

Protective Mechanism ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Duct Ligation ◽

Associated Proteins ◽

Anti Inflammatory ◽

Cholestatic Liver Injury

Cholestatic liver injury, due to obstruction of the biliary tract or genetic defects, is often accompanied by progressive inflammation and liver fibrosis. Methane-rich saline (MRS) has anti-inflammatory properties. However, whether MRS can provide protective effect in cholestatic liver injury is still unclear. In this study, Sprague-Dawley rats received bile duct ligation (BDL) to generate a cholestatic model followed by MRS treatment (10 mL/kg, ip treatment) every 12 h after the operation to explore the potential protective mechanism of MRS in cholestatic liver injury. We found that MRS effectively improved liver function, alleviated liver pathological damage, and localized infiltration of inflammatory cells. MRS treatment decreased the expression of hepatic fibrosis-associated proteins to alleviate liver fibrosis. Furthermore, MRS treatment suppressed the TLR4/NF-κB pathway and further reduced the levels of proinflammatory factors. Downregulation of NF-κB subsequently reduced the NLRP3 expression to inhibit pyroptosis. Our data indicated that methane treatment prevented cholestatic liver injury via anti-inflammatory properties that involved the TLR4/NF-κB/NLRP3 signaling pathway.

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Flavanones from Sedum sarmentosum Bunge Alleviate CCl4-Induced Liver Fibrosis in Rats by Targeting TGF-β1/TβR/Smad Pathway In Turn Inhibiting Epithelial Mesenchymal Transition

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/3080837 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Yuancan Lin ◽

Haiying Luo ◽

Xiao Wang ◽

Minxia Zheng ◽

Qianxing Jin ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Tissue ◽

Epithelial Mesenchymal Transition ◽

Inflammatory Cells ◽

Therapeutic Effects ◽

Smad Pathway ◽

Mesenchymal Transition ◽

Serum Biochemical ◽

Underlying Mechanisms ◽

Mean Time

Objective. The aim of the study is to evaluate the therapeutic effects of flavanones from Sedum sarmentosum Bunge (FSSB) on CCl4-induced liver fibrosis in rats and the underlying mechanisms of action. Methods. An experimental model of liver fibrosis was established by subcutaneous injection of rats with CCl4 (40% v/v, 3 ml/kg) twice per week for six weeks. FSSB (100, 200, and 400 mg/kg) was intragastrically administered once per day consecutively for five weeks. Results. Our results showed that FSSB significantly attenuated CCl4-induced liver fibrosis as evidenced by reducing the elevated levels of serum biochemical indexes and improving the histological changes, including decreasing the elevation in serum alanine transaminase (ALT), aspartate transaminase (AST), hyaluronic acid (HA), and laminin (LN) level, reducing infiltration of inflammatory cells and collagen fibers in liver tissue. In addition, compared to the model group, FSSB markedly downregulated the protein and mRNA expression of TGF-β1, TGF-β1 receptors I and II (TβRI and TβRII), Smad2, Smad3, and Vimentin in liver tissue, at the mean time upregulating the expression of Smad7 and E-cadherin. Conclusions. The results suggest that FSSB alleviated CCl4-induced liver fibrosis probably through inhibition of TGF-β/TβR/Smad pathway in turn inhibiting epithelial mesenchymal transition.

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Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

Cell Death and Disease ◽

10.1038/s41419-021-04403-2 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Xuejiao Chen ◽

Ziyi Wang ◽

Sheng Han ◽

Zeng Wang ◽

Yu Zhang ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

High Frequency ◽

Inflammatory Cells ◽

Danger Signal ◽

Dual Inhibitor ◽

Fibrotic Liver ◽

Cancer Occurrence ◽

Duct Ligation ◽

Syk Inhibitor

AbstractLiver fibrosis is a danger signal indicating a huge risk of liver cancer occurrence, but there is still no effective clinical means to regulate the progress of liver fibrosis. Although a variety of drugs targeting SYK have been developed for tumors and autoimmune diseases, the mechanism and specific efficacy of SYK’s role in liver fibrosis are not yet clear. Our studies based on chronic CCL4, bile duct ligation, and subacute TAA mouse models show that SYK in monocyte-derived macrophages (MoMFs) is fully dependent on phosphorylation of Erk to up-regulate the expression of Hif1α, thereby forming the crosstalk with SYK to drive liver fibrosis progress. We have evaluated the ability of the small molecule SYK inhibitor GS9973 in a variety of models. Contrary to previous impressions, high-frequency administration of GS9973 will aggravate CCL4-induced liver fibrosis, which is especially unsuitable for patients with cholestasis whose clinical features are bile duct obstruction. In addition, we found that inhibition of MoMFs SYK impairs the expression of CXCL1, on one hand, it reduces the recruitment of CD11bhiLy6Chi inflammatory cells, and on the other hand, it promotes the phenotype cross-dress process of pro-resolution MoMFs, thereby remodeling the chronic inflammatory environment of the fibrotic liver. Our further findings indicate that on the basis of the administration of CCR2/CCR5 dual inhibitor Cenicriviroc, further inhibiting MoMFs SYK may give patients with fibrosis additional benefits.

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Faculty Opinions recommendation of A contradictory role of A1 adenosine receptor in carbon tetrachloride- and bile duct ligation-induced liver fibrosis in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1345984.817085 ◽

2009 ◽

Author(s):

Jonathan A Dranoff

Keyword(s):

Carbon Tetrachloride ◽

Bile Duct ◽

Liver Fibrosis ◽

Adenosine Receptor ◽

Bile Duct Ligation ◽

A1 Adenosine Receptor ◽

Duct Ligation

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Faculty Opinions recommendation of Glucocorticoids have opposing effects on liver fibrosis in hepatic stellate and immune cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726471146.793520459 ◽

2016 ◽

Author(s):

Karen Chapman

Keyword(s):

Liver Fibrosis ◽

Immune Cells ◽

Opposing Effects

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Adenoviral CCN3/NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis

Liver International ◽

10.1111/j.1478-3231.2012.02837.x ◽

2012 ◽

Vol 32 (9) ◽

pp. 1342-1353 ◽

Cited By ~ 14

Author(s):

Erawan Borkham-Kamphorst ◽

Sebastian Huss ◽

Eddy Leur ◽

Ute Haas ◽

Ralf Weiskirchen

Keyword(s):

Bile Duct ◽

Gene Transfer ◽

Liver Fibrosis ◽

Bile Duct Ligation ◽

Hepatocyte Apoptosis ◽

Duct Ligation

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Hyperthermia by near infrared radiation induced immune cells activation and infiltration in breast tumor

Scientific Reports ◽

10.1038/s41598-021-89740-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wan Fatin Amira Wan Mohd Zawawi ◽

M. H. Hibma ◽

M. I. Salim ◽

K. Jemon

Keyword(s):

Breast Cancer ◽

T Cells ◽

Side Effects ◽

Immune Cells ◽

Infrared Radiation ◽

Near Infrared ◽

Tumor Regression ◽

Immunohistochemical Analysis ◽

Therapeutic Effects ◽

Near Infrared Radiation

AbstractBreast cancer is the most common cancer that causes death in women. Conventional therapies, including surgery and chemotherapy, have different therapeutic effects and are commonly associated with risks and side effects. Near infrared radiation is a technique with few side effects that is used for local hyperthermia, typically as an adjuvant to other cancer therapies. The understanding of the use of near NIR as a monotherapy, and its effects on the immune cells activation and infiltration, are limited. In this study, we investigate the effects of HT treatment using NIR on tumor regression and on the immune cells and molecules in breast tumors. Results from this study demonstrated that local HT by NIR at 43 °C reduced tumor progression and significantly increased the median survival of tumor-bearing mice. Immunohistochemical analysis revealed a significant reduction in cells proliferation in treated tumor, which was accompanied by an abundance of heat shock protein 70 (Hsp70). Increased numbers of activated dendritic cells were observed in the draining lymph nodes of the mice, along with infiltration of T cells, NK cells and B cells into the tumor. In contrast, tumor-infiltrated regulatory T cells were largely diminished from the tumor. In addition, higher IFN-γ and IL-2 secretion was observed in tumor of treated mice. Overall, results from this present study extends the understanding of using local HT by NIR to stimulate a favourable immune response against breast cancer.

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How Changes in the Nutritional Landscape Shape Gut Immunometabolism

Nutrients ◽

10.3390/nu13030823 ◽

2021 ◽

Vol 13 (3) ◽

pp. 823

Author(s):

Jian Tan ◽

Duan Ni ◽

Rosilene V. Ribeiro ◽

Gabriela V. Pinget ◽

Laurence Macia

Keyword(s):

Immune Cells ◽

Metabolic Pathways ◽

Immune Cell ◽

Food Additives ◽

Cell Activity ◽

Inflammatory Cells ◽

Therapeutic Approaches ◽

Food Antigens ◽

And Function ◽

Micro Organisms

Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.

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Low-Dose Radiotherapy for Late-Stage COVID-19 Pneumonia?

Dose-Response ◽

10.1177/1559325820951357 ◽

2020 ◽

Vol 18 (3) ◽

pp. 155932582095135

Author(s):

Michael I. Koukourakis

Keyword(s):

Respiratory Failure ◽

Immune Cells ◽

Late Stage ◽

Low Dose ◽

Inflammatory Cells ◽

Lung Parenchyma ◽

Death Rates ◽

Low Dose Radiotherapy ◽

Therapeutic Value ◽

Inflammatory Effect

Low dose radiotherapy has been used in the pre-antibiotic era for the treatment of all kind of pneumonia, with relative success. The unimaginable daily death toll of thousands of victims dying from COVID-19 pneumonia and the marginal therapeutic value of agents tested, brings forward the re-evaluation of the position of radiotherapy in the treatment of late stage lethal COVID-induced respiratory failure. A sound biological rationale supports this idea. Immunopathology studies show that excessive inflammation and infiltration of the lung parenchyma by immune cells is the cause of death. Mice lacking IFNαβ receptors remain unaffected by the virus. Radiotherapy at doses of 50-200cG may exert an intense anti-inflammatory effect and reduce the burden of inflammatory cells infiltrating the lungs. Whether radiotherapy, in conjunction with remdesivir and/or macrolides can reduce the dramatic death rates related to COVID-19 is an open challenge, under the absence of an alternative solution.

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