Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

2018 ◽  
Vol 3 (28) ◽  
pp. eaar7754 ◽  
Author(s):  
Thomas Fabre ◽  
Manuel Flores Molina ◽  
Geneviève Soucy ◽  
Jean-Philippe Goulet ◽  
Bernard Willems ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Orphan Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Adaptive Immune Cells ◽  
Type 3

Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor–β signaling in HSCs in a p38 mitogen-activated protein kinase–dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.

scholarly journals TGF-β1 Induces the Dual Regulation of Hepatic Progenitor Cells with Both Anti- and Proliver Fibrosis

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Ai-Ting Yang ◽  
Dou-Dou Hu ◽  
Ping Wang ◽  
Min Cong ◽  
Tian-Hui Liu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Progenitor Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Dependent Manner ◽  
Hepatic Progenitor Cells ◽  
Serum Aminotransferase ◽  
Dose Dependent

Transforming growth factor-beta 1 (TGF-β1) plays a central role in hepatic progenitor cells- (HPCs-) mediated liver repair and fibrosis. However, different effects of TGF-β1 on progenitor cells have not been described. In this study, both in vitro (HPCs cocultured with hepatic stellate cells (HSCs) in transwells) and in vivo (CCl4-injured liver fibrosis rat) systems were used to evaluate the impacts. We found that HPCs pretreated with TGF-β1 for 12 hours inhibited the activation of HSCs, while sensitization for 48 hours increased the activation of HSCs. Consistent with these in vitro results, the in vivo fibrosis rat model showed the same time-dependent dual effect of TGF-β1. Regression of liver fibrosis as well as normalization of serum aminotransferase and albumin levels was detected in the rats transplanted with HPCs pretreated with TGF-β1 for 12 hours. In contrast, severe liver fibrosis and elevated collagen-1 levels were detected in the rats transplanted with HPCs pretreated with TGF-β1 for 48 hours. Furthermore, the TGF-β1-pretreated HPCs were shown to deactivate HSCs via enhancing SERPINE1 expression. Inhibition of SERPINE1 reversed the deactivation response in a dose-dependent manner.

scholarly journals MiR-130a-3p Alleviates Liver Fibrosis by Suppressing HSCs Activation and Skewing Macrophage to Ly6Clo Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei Liu ◽  
Peng Wang ◽  
Yun-Sheng Wang ◽  
Ya-Nan Zhang ◽  
Chen Li ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Granulomatous Inflammation ◽  
Mitogen Activated Protein Kinase ◽  
Potential Candidate ◽  
Mitogen Activated Protein

Emerging evidences have highlighted the crucial role of microRNAs (miRNAs) in the liver cirrhosis, but the relationship between miR-130a-3p and liver cirrhosis is not entirely clear. As we all know, schistosomiasis, as one of the zoonoses, can lead to liver cirrhosis when it advances. In this study, we investigated the biological functions of miR-130a-3p on the liver fibrosis of schistosomiasis in vivo and in vitro. The mice infected with Schistosoma japonicum (S. japonicum) were treated with lentivirus vector (LV)-miR-130a-3p by hydrodynamic injection through the tail vein. Our findings showed significantly decreased expression of miR-130a-3p both in the serum of patients with cirrhosis and in the liver of mice infected with S. japonicum. The results showed that LV-miR-130a-3p could effectively enter into the liver and alleviate liver granulomatous inflammation and collagen deposition. Simultaneously, LV-miR-130a-3p-promoted macrophages presented the Ly6Clo phenotype, concomitant with the decreased expression of the tissue inhibitor of metalloproteinases (TIMP) 1, and increased the expression of matrix metalloproteinase (MMP) 2, which contributed to the dissolution of collagen. Furthermore, overexpression of miR-130a-3p not only inhibited the activation and proliferation of hepatic stellate cells (HSCs) but also induced the apoptosis of HSCs. In addition, we also confirmed that miR-130a-3p enables to bind with mitogen-activated protein kinase (MAPK) 1 and transforming growth factor-beta receptors (TGFBR) 1 and TGFBR2 genes and inhibit the expressions of these genes. Our findings suggested that miR-130a-3p might represent as the potential candidate biomarker and therapeutic target for the prognosis identification and treatment of schistosomiasis liver fibrosis.

scholarly journals Naringenin: A Promising Therapeutic Agent against Organ Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yanfei Du ◽  
Jun Ma ◽  
Yu Fan ◽  
Xinyu Wang ◽  
Shuzhan Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Developed Countries ◽  
Mitogen Activated Protein Kinase ◽  
Drug Candidate ◽  
Wide Range ◽  
Fibrotic Disorders ◽  
Organ Fibrosis

Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.

scholarly journals INTEGRINS MEDIATE PLACENTAL EXTRACELLULAR VESICLE TRAFFICKING TO LUNG AND LIVER IN VIVO

2020 ◽  
Author(s):  
Sean L. Nguyen ◽  
Soo Hyun Ahn ◽  
Jacob W. Greenberg ◽  
Benjamin W. Collaer ◽  
Dalen W. Agnew ◽  
...  
Keyword(s):  
Immune Cells ◽  
Extracellular Vesicle ◽  
Dependent Manner ◽  
Cellular Phenotype ◽  
Reporter Mouse ◽  
Membrane Bound ◽  
First Time

ABSTRACTMembrane-bound extracellular vesicles (EVs) mediate intercellular communication in all organisms, and those produced by placental mammals have become increasingly recognized as significant mediators of fetal-maternal communication. Here, we aimed to identify maternal cells targeted by placental EVs and elucidate the mechanisms by which they traffic to these cells. Exogenously administered pregnancy-associated EVs traffic specifically to the lung; further, placental EVs associate with lung interstitial macrophages and liver Kupffer cells in an integrin-dependent manner. Localization of EV to maternal lungs was confirmed in unmanipulated pregnancy using a transgenic reporter mouse model, which also provided in situ and in vitro evidence that fetally-derived EVs, rarely, may cause genetic alteration of maternal cells. These results provide for the first time direct in vivo evidence for targeting of placental EVs to maternal immune cells, and further, evidence that EVs can alter cellular phenotype.

scholarly journals Extracellular Signal-Regulated Kinases Phosphorylate Mitogen-Activated Protein Kinase Phosphatase 3/DUSP6 at Serines 159 and 197, Two Sites Critical for Its Proteasomal Degradation

2005 ◽  
Vol 25 (2) ◽  
pp. 854-864 ◽  
Author(s):  
Sandrine Marchetti ◽  
Clotilde Gimond ◽  
Jean-Claude Chambard ◽  
Thomas Touboul ◽  
Danièle Roux ◽  
...  
Keyword(s):  
Map Kinases ◽  
Fluorescent Protein ◽  
Proteasomal Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Double Mutation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein (MAP) kinase phosphatases (MKPs) are dual-specificity phosphatases that dephosphorylate phosphothreonine and phosphotyrosine residues within MAP kinases. Here, we describe a novel posttranslational mechanism for regulating MKP-3/Pyst1/DUSP6, a member of the MKP family that is highly specific for extracellular signal-regulated kinase 1 and 2 (ERK1/2) inactivation. Using a fibroblast model in which the expression of either MKP-3 or a more stable MKP-3-green fluorescent protein (GFP) chimera was induced by tetracycline, we found that serum induces the phosphorylation of MKP-3 and its subsequent degradation by the proteasome in a MEK1 and MEK2 (MEK1/2)-ERK1/2-dependent manner. In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197. Tetracycline-inducible cell clones expressing either single or double serine mutants of MKP-3 or MKP-3-GFP confirmed that these two sites are targeted by the MEK1/2-ERK1/2 module in vivo. Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. Hence, double mutation caused a threefold increase in the half-life of MKP-3. Finally, we show that the phosphorylation of MKP-3 has no effect on its catalytic activity. Thus, ERK1/2 exert a positive feedback loop on their own activity by promoting the degradation of MKP-3, one of their major inactivators in the cytosol, a situation opposite to that described for the nuclear phosphatase MKP-1.

scholarly journals p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression

2008 ◽  
Vol 183 (4) ◽  
pp. 737-749 ◽  
Author(s):  
Edwin Soto ◽  
Masahiro Yanagisawa ◽  
Laura A. Marlow ◽  
John A. Copland ◽  
Edith A. Perez ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Tumor Cell Growth ◽  
P120 Catenin ◽  
Opposing Effects ◽  
E Cadherin

p120 catenin regulates the activity of the Rho family guanosine triphosphatases (including RhoA and Rac1) in an adhesion-dependent manner. Through this action, p120 promotes a sessile cellular phenotype when associated with epithelial cadherin (E-cadherin) or a motile phenotype when associated with mesenchymal cadherins. In this study, we show that p120 also exerts significant and diametrically opposing effects on tumor cell growth depending on E-cadherin expression. Endogenous p120 acts to stabilize E-cadherin complexes and to actively promote the tumor-suppressive function of E-cadherin, potently inhibiting Ras activation. Upon E-cadherin loss during tumor progression, the negative regulation of Ras is relieved; under these conditions, endogenous p120 promotes transformed cell growth both in vitro and in vivo by activating a Rac1–mitogen-activated protein kinase signaling pathway normally activated by the adhesion of cells to the extracellular matrix. These data indicate that both E-cadherin and p120 are important regulators of tumor cell growth and imply roles for both proteins in chemoresistance and targeted therapeutics.

Physical plasma and leukocytes – immune or reactive?

2018 ◽  
Vol 400 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Sander Bekeschus ◽  
Christian Seebauer ◽  
Kristian Wende ◽  
Anke Schmidt
Keyword(s):  
Wound Healing ◽  
Immune System ◽  
Plasma Treatment ◽  
Immune Cells ◽  
The Body ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Physical Plasma

AbstractLeukocytes are professionals in recognizing and removing pathogenic or unwanted material. They are present in virtually all tissues, and highly motile to enter or leave specific sites throughout the body. Less than a decade ago, physical plasmas entered the field of medicine to deliver their delicate mix of reactive species and other physical agents for mainly dermatological or oncological therapy. Plasma treatment thus affects leukocytes via direct or indirect means: immune cells are either present in tissues during treatment, or infiltrate or exfiltrate plasma-treated areas. The immune system is crucial for human health and resolution of many types of diseases. It is therefore vital to study the response of leukocytes after plasma treatmentin vitroandin vivo. This review gathers together the major themes in the plasma treatment of innate and adaptive immune cells, and puts these into the context of wound healing and oncology, the two major topics in plasma medicine.

scholarly journals Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Zhemin Shi ◽  
Kun Zhang ◽  
Ting Chen ◽  
Yu Zhang ◽  
Xiaoxiao Du ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
In Vitro Study ◽  
Stellate Cells ◽  
Protective Role ◽  
Activating Transcription Factor 3 ◽  
Dependent Manner ◽  
Liver Fibrogenesis

AbstractThe excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis.

scholarly journals Suppression of the TGF-β pathway by a macrolide antibiotic decreases fibrotic responses by ocular fibroblasts in vitro

2020 ◽  
Vol 7 (9) ◽  
pp. 200441
Author(s):  
Thomas Stahnke ◽  
Beata Gajda-Deryło ◽  
Anselm G. Jünemann ◽  
Oliver Stachs ◽  
Katharina A. Sterenczak ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Macrolide Antibiotic ◽  
Drug Repositioning ◽  
Dependent Manner ◽  
Glaucoma Filtration Surgery ◽  
Concentration Dependent Manner ◽  
Device Implantation

To elucidate and to inhibit post-surgical fibrotic processes after trabeculectomy in glaucoma therapy, we measured gene expression in a fibrotic cell culture model, based on transforming growth factor TGF-β induction in primary human tenon fibroblasts (hTFs), and used Connectivity Map (CMap) data for drug repositioning. We found that specific molecular mechanisms behind fibrosis are the upregulation of actins, the downregulation of CD34, and the upregulation of inflammatory cytokines such as IL6, IL11 and BMP6 . The macrolide antibiotic Josamycin (JM) reverses these molecular mechanisms according to data from the CMap, and we thus tested JM as an inhibitor of fibrosis. JM was first tested for its toxic effects on hTFs, where it showed no influence on cell viability, but inhibited hTF proliferation in a concentration-dependent manner. We then demonstrated that JM suppresses the synthesis of extracellular matrix (ECM) components. In hTFs stimulated with TGF-β1, JM specifically inhibited α-smooth muslce actin expression, suggesting that it inhibits the transformation of fibroblasts into fibrotic myofibroblasts. In addition, a decrease of components of the ECM such as fibronectin, which is involved in in vivo scarring, was observed. We conclude that JM may be a promising candidate for the treatment of fibrosis after glaucoma filtration surgery or drainage device implantation in vivo .

scholarly journals The immunoregulation of mesenchymal stem cells plays a critical role in improving the prognosis of liver transplantation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chenxia Hu ◽  
Lanjuan Li
Keyword(s):  
Liver Transplantation ◽  
Natural Killer ◽  
Immune Cells ◽  
Adaptive Systems ◽  
Critical Role ◽  
Arterial System ◽  
Cell Mediated Immunity ◽  
Adaptive Immune Cells

AbstractThe liver is supplied by a dual blood supply, including the portal venous system and the hepatic arterial system; thus, the liver organ is exposed to multiple gut microbial products, metabolic products, and toxins; is sensitive to extraneous pathogens; and can develop liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) after short-term or long-term injury. Although liver transplantation (LT) serves as the only effective treatment for patients with end-stage liver diseases, it is not very popular because of the complications and low survival rates. Although the liver is generally termed an immune and tolerogenic organ with adaptive systems consisting of humoral immunity and cell-mediated immunity, a high rejection rate is still the main complication in patients with LT. Growing evidence has shown that mesenchymal stromal cell (MSC) transplantation could serve as an effective immunomodulatory strategy to induce tolerance in various immune-related disorders. MSCs are reported to inhibit the immune response from innate immune cells, including macrophages, dendritic cells (DCs), natural killer cells (NK cells), and natural killer T (NKT) cells, and that from adaptive immune cells, including T cells, B cells and other liver-specific immune cells, for the generation of a tolerogenic microenvironment. In this review, we summarized the relationship between LT and immunoregulation, and we focused on how to improve the effects of MSC transplantation to improve the prognosis of LT. Only after exhaustive clarification of the potential immunoregulatory mechanisms of MSCs in vitro and in vivo can we implement MSC protocols in routine clinical practice to improve LT outcome.

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