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Li Y, Li TY, Qiao Q, Zhang MT, Tong MX, Xu LF, Zhang ZB. Polymeric immunoglobulin receptor promotes Th2 immune response in the liver by increasing cholangiocytes derived IL-33: a diagnostic and therapeutic biomarker of biliary atresia. EBioMedicine 2024; 108:105344. [PMID: 39288533 PMCID: PMC11421278 DOI: 10.1016/j.ebiom.2024.105344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Biliary atresia (BA) is a devastating neonatal cholangiopathy with an unclear pathogenesis, and prompt diagnosis of BA is currently challenging. METHODS Proteomic and immunoassay analyses were performed with serum samples from 250 patients to find potential BA biomarkers. The expression features of polymeric immunoglobulin receptor (PIGR) were investigated using human biopsy samples, three different experimental mouse models, and cultured human biliary epithelial cells (BECs). Chemically modified small interfering RNA and adenovirus expression vector were applied for in vivo silencing and overexpressing PIGR in a rotavirus-induced BA mouse model. Luminex-based multiplex cytokine assays and RNA sequencing were used to explore the molecular mechanism of PIGR involvement in the BA pathogenesis. FINDINGS Serum levels of PIGR, poliovirus receptor (PVR), and aldolase B (ALDOB) were increased in BA patients and accurately distinguished BA from infantile hepatitis syndrome (IHS). Combined PIGR and PVR analysis distinguished BA from IHS with an area under the receiver operating characteristic curve of 0.968 and an accuracy of 0.935. PIGR expression was upregulated in the biliary epithelium of BA patients; Th1 cytokines TNF-α and IFN-γ induced PIGR expression in BECs via activating NF-κB pathway. Silencing PIGR alleviated symptoms, reduced IL-33 expression, and restrained hepatic Th2 inflammation in BA mouse model; while overexpressing PIGR increased liver fibrosis and IL-33 expression, and boosted hepatic Th2 inflammation in BA mouse model. PIGR expression promotes the proliferation and epithelial-mesenchymal transition, and reduced the apoptosis of BECs. INTERPRETATION PIGR participated in BA pathogenesis by promoting hepatic Th2 inflammation via increasing cholangiocytes derived IL-33; PIGR has the value as a diagnostic and therapeutic biomarker of BA. FUNDING This study was financially supported by the National Natural Science Foundation of China (82170529), the National Key R&D Program (2021YFC2701003), and the National Natural Science Foundation of China (82272022).
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Affiliation(s)
- Yuan Li
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Tian-Yu Li
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Qi Qiao
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Min-Ting Zhang
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Ming-Xin Tong
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Ling-Fen Xu
- Department of Paediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China
| | - Zhi-Bo Zhang
- Department of Paediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, PR China.
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Apoptotic biliary epithelial cells and gut dysbiosis in the induction of murine primary biliary cholangitis. J Transl Autoimmun 2022; 6:100182. [PMID: 36619656 PMCID: PMC9811212 DOI: 10.1016/j.jtauto.2022.100182] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive Firmicutes in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.
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Chen R, Tang R, Ma X, Gershwin ME. Immunologic Responses and the Pathophysiology of Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:583-611. [PMID: 36270718 DOI: 10.1016/j.cld.2022.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease with a female predisposition and selective destruction of intrahepatic small bile ducts leading to nonsuppurative destructive cholangitis. It is characterized by seropositivity of antimitochondrial antibodies or PBC-specific antinuclear antibodies, progressive cholestasis, and typical liver histologic manifestations. Destruction of the protective bicarbonate-rich umbrella is attributed to the decreased expression of membrane transporters in biliary epithelial cells (BECs), leading to the accumulation of hydrophobic bile acids and sensitizing BECs to apoptosis. A recent X-wide association study reveals a novel risk locus on the X chromosome, which reiterates the importance of Treg cells.
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Affiliation(s)
- Ruiling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China.
| | - M Eric Gershwin
- Division of Rheumatology-Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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Guatibonza-García V, Gaete PV, Pérez-Londoño A, Puerto-Baracaldo DK, Gutiérrez-Romero SA, Mendivil CO, Tapias M. Poor performance of anti-mitochondrial antibodies for the diagnosis of primary biliary cholangitis in female Colombian patients: A single-center study. World J Gastroenterol 2021; 27:4890-4899. [PMID: 34447233 PMCID: PMC8371498 DOI: 10.3748/wjg.v27.i29.4890] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/03/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a serious disease that causes significant morbidity. PBC is confirmed with liver biopsy but autoantibodies are frequently used as proxies for diagnosis. The performance of autoantibodies for the diagnosis of PBC seems to vary widely across populations.
AIM To assess the diagnostic performance of several autoantibodies for the diagnosis of PBC in Latin American individuals.
METHODS We studied 85 female adult Colombians, 43 cases with biopsy-confirmed PBC and 42 controls in whom a liver biopsy ruled out PBC. Plasma anti-mitochondrial antibodies (AMAs), anti-smooth muscle antibodies (ASMAs) and anti-nuclear antibodies (ANAs), as well as total immunoglobulin (Ig) M and IgG were determined using immunofluorescence or enzyme-linked immunosorbent assay in all study participants within 1 year of the biopsy. For all variables, values analyzed were those closest to the date of the biopsy. Patients with viral or alcoholic hepatitis were excluded.
RESULTS Mean age at diagnosis was 58.7 years for cases and 56.9 years for controls, and the body mass index was lower among cases. Most cases received ursodeoxycholic acid, while most controls received vitamin E. Sjögren syndrome and Hashimoto’s thyroiditis were the most frequent autoimmune comorbidities of PBC. The prevalence of AMA positivity among PBC cases was unexpectedly low. The sensitivity and specificity values were respectively 44.2% and 76.2% for AMA, 74.4% and 38.1% for ANA, 14.0% and 73.8% for ASMA, 26.7% and 80.0% for IgG, and 57.1% and 85.7% for IgM. The combination of positive AMA plus positive IgM had 91% positive predictive value for PBC. Among AMA-negative cases, the most prevalent antibodies were ANA (87.5%). In all, 62% of AMA-positive and 84.6% of IgM-positive individuals had fibrosis in their biopsy.
CONCLUSION AMA positivity was very low among female Latin American patients with PBC. The performance of all antibodies was quite limited. These results highlight the urgent need for better PBC biomarkers.
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Affiliation(s)
| | | | | | | | | | - Carlos O Mendivil
- Section of Endocrinology, Department of Internal Medicine, Fundación Santa Fe de Bogotá, Bogotá 110111, Colombia
| | - Monica Tapias
- School of Medicine, Universidad de los Andes, Bogotá 110111, Colombia
- Department of Hepatology, Fundación Santa Fe de Bogotá, Bogotá 110111, Colombia
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Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway. Cell Biosci 2020; 10:43. [PMID: 32206298 PMCID: PMC7083051 DOI: 10.1186/s13578-020-00402-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background Induction of biliary epithelial cell apoptosis by toxic bile acids is involved in the development of cholestatic disease, but the underlying molecular mechanism is not clear. The purpose of this study was to investigate the molecular mechanisms involved in Sirt6 protection against the apoptosis of human intrahepatic biliary epithelial cells (HiBEC) induced by the bile acid glycochenodeoxycholate (GCDC). Results Sirt6 was either overexpressed or knocked down in HiBEC, with or without GCDC pretreatment. The CCK-8 assay was used to assess cell viability and, Hoechst 33258 staining was used to determine apoptotic rate. Mitochondrial DNA (mtDNA) copy number, malondialdehyde (MDA) and reactive oxygen species (ROS) production were detected to evaluate the severity of the mitochondrial dysfunction and oxidative stress. The mRNA and protein levels of PGC-1α, Nrf1, and Nrf2 were analyzed using RT-qPCR and western blot assay. The results showed that Sirt6 opposed GCDC-induced apoptosis in HiBEC via up-regulating PGC-1α expression and stabilizing mtDNA. We used agonists and inhibitors of AMPK to demonstrate that Sirt6 increased PGC-1α expression through the AMPK pathway whereas GCDC had the opposite effect. Finally, western blot, luciferase assay, and co-immunoprecipitation were used to describe a direct interaction and acetylation modification of PGC-1α by Sirt6. Conclusion Our data illuminated that Sirt6 ameliorated GCDC-induced HiBEC apoptosis by upregulating PGC-1α expression through the AMPK pathway and its deacetylation effect.
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Fiorotto R, Strazzabosco M. Pathophysiology of Cystic Fibrosis Liver Disease: A Channelopathy Leading to Alterations in Innate Immunity and in Microbiota. Cell Mol Gastroenterol Hepatol 2019; 8:197-207. [PMID: 31075352 PMCID: PMC6664222 DOI: 10.1016/j.jcmgh.2019.04.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 12/12/2022]
Abstract
Cystic fibrosis (CF) is a monogenic disease caused by mutation of Cftr. CF-associated liver disease (CFLD) is a common nonpulmonary cause of mortality in CF and accounts for approximately 2.5%-5% of overall CF mortality. The peak of the disease is in the pediatric population, but a second wave of liver disease in CF adults has been reported in the past decade in association with an increase in the life expectancy of these patients. New drugs are available to correct the basic defect in CF but their efficacy in CFLD is not known. The cystic fibrosis transmembrane conductance regulator, expressed in the apical membrane of cholangiocytes, is a major determinant for bile secretion and CFLD classically has been considered a channelopathy. However, the recent findings of the cystic fibrosis transmembrane conductance regulator as a regulator of epithelial innate immunity and the possible influence of the intestinal disease with an altered microbiota on the liver complication have opened new mechanistic insights on the pathogenesis of CFLD. This review provides an overview of the current understanding of the pathophysiology of the disease and discusses a potential target for intervention.
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Affiliation(s)
- Romina Fiorotto
- Section of Digestive Diseases, Yale Liver Center, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
| | - Mario Strazzabosco
- Section of Digestive Diseases, Yale Liver Center, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
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Zhu H, Chai Y, Dong D, Zhang N, Liu W, Ma T, Wu R, Lv Y, Hu L. AICAR-Induced AMPK Activation Inhibits the Noncanonical NF-κB Pathway to Attenuate Liver Injury and Fibrosis in BDL Rats. Can J Gastroenterol Hepatol 2018; 2018:6181432. [PMID: 30662889 PMCID: PMC6314002 DOI: 10.1155/2018/6181432] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/17/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND To evaluate the AMP-activated protein kinase- (AMPK-) mediated signaling and NF-κB-related inflammatory pathways that contribute to cholestatic diseases in the bile duct ligation (BDL) rat model of chronic cholestasis and verify the protective role of 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) against hepatic injury and fibrosis triggered by cholestasis-related inflammation. METHODS Animals were randomly divided into three groups: sham-operated group, BDL group, and BDL+ AICAR group. Cholestatic liver injury was induced by common BDL. Two weeks later, rats in BDL+AICAR group started receiving AICAR treatment. Hepatic pathology was examined by haematoxylin and eosin (H&E) and sirius red staining and hydroxyproline assay was performed in evaluating the severity of hepatic cirrhosis. Real-time PCR and Western blot were performed for RNA gene expression of RNA and protein levels, respectively. RESULTS The BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, and inflammation. The mRNA expression of canonical NF-κB inflammatory cytokines such as TNF-α, IL-1β, TGF-β, and the protein of noncanonical NF-κB, P100, and P52 was upregulated in the livers of BDL rats. The BDL rats with the administration of AICAR could induce AMPK activation inhibiting the noncanonical NF-κB pathway to attenuate liver injury and fibrosis in BDL rats. CONCLUSION The BDL model of hepatic cholestatic injury resulting in activation of Kupffer cells and recruitment of immune cells might initiate an inflammatory response through activation of the NF-κB pathway. The AMPK activator AICAR significantly alleviated BDL-induced inflammation in rats by mainly inhibiting the noncanonical NF-κB pathway and thus protecting against hepatic injury and fibrosis triggered by BDL.
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Affiliation(s)
- Haoyang Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Yichao Chai
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Dinghui Dong
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Nana Zhang
- Institute for Cancer Research School of Basic Medical Science of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Wenyan Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Tao Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
| | - Liangshuo Hu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi'an 710061, Shaanxi Province, China
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Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:17-25. [PMID: 30343706 DOI: 10.1016/j.bpg.2018.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, 200 Elizabeth Street, Toronto, ON, Canada.
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.
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Zhang H, Leung PSC, Gershwin ME, Ma X. How the biliary tree maintains immune tolerance? Biochim Biophys Acta Mol Basis Dis 2017; 1864:1367-1373. [PMID: 28844953 DOI: 10.1016/j.bbadis.2017.08.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/03/2017] [Accepted: 08/09/2017] [Indexed: 12/27/2022]
Abstract
The liver is a vital organ with distinctive anatomy, histology and heterogeneous cell populations. These characteristics are of particular importance in maintaining immune homeostasis within the liver microenvironments, notably the biliary tree. Cholangiocytes are the first line of defense of the biliary tree against foreign substances, and are equipped to participate through various immunological pathways. Indeed, cholangiocytes protect against pathogens by TLRs-related signaling; maintain tolerance by expression of IRAK-M and PPARγ; limit immune response by inducing apoptosis of leukocytes; present antigen by expressing human leukocyte antigen molecules and costimulatory molecules; recruit leukocytes to the target site by expressing cytokines and chemokines. However, breach of tolerance in the biliary tree results in various cholangiopathies, exemplified by primary biliary cholangitis, primary sclerosing cholangitis and biliary atresia. Lessons learned from immune tolerance of the biliary tree will provide the basis for the development of effective therapeutic approaches against autoimmune biliary tract diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Haiyan Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 145 Middle Shandong Road, Shanghai 200001, China
| | - Patrick S C Leung
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease; 145 Middle Shandong Road, Shanghai 200001, China.
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Yoo KS, Lim WT, Choi HS. Biology of Cholangiocytes: From Bench to Bedside. Gut Liver 2017; 10:687-98. [PMID: 27563020 PMCID: PMC5003190 DOI: 10.5009/gnl16033] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/14/2016] [Accepted: 03/09/2016] [Indexed: 12/11/2022] Open
Abstract
Cholangiocytes, the lining epithelial cells in bile ducts, are an important subset of liver cells. They are activated by endogenous and exogenous stimuli and are involved in the modification of bile volume and composition. They are also involved in damaging and repairing the liver. Cholangiocytes have many functions including bile production. They are also involved in transport processes that regulate the volume and composition of bile. Cholangiocytes undergo proliferation and cell death under a variety of conditions. Cholangiocytes have functional and morphological heterogenecity. The immunobiology of cholangiocytes is important, particularly for understanding biliary disease. Secretion of different proinflammatory mediators, cytokines, and chemokines suggests the major role that cholangiocytes play in inflammatory reactions. Furthermore, paracrine secretion of growth factors and peptides mediates extensive cross-talk with other liver cells, including hepatocytes, stellate cells, stem cells, subepithelial myofibroblasts, endothelial cells, and inflammatory cells. Cholangiopathy refers to a category of chronic liver diseases whose primary disease target is the cholangiocyte. Cholangiopathy usually results in end-stage liver disease requiring liver transplant. We summarize the biology of cholangiocytes and redefine the concept of cholangiopathy. We also discuss the recent progress that has been made in understanding the pathogenesis of cholangiopathy and how such progress has influenced therapy.
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Affiliation(s)
- Kyo-Sang Yoo
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Woo Taek Lim
- Korea University School of Medicine, Seoul, Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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11
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Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1374-1379. [PMID: 28754453 DOI: 10.1016/j.bbadis.2017.07.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022]
Abstract
The most studied physiological function of biliary epithelial cells (cholangiocytes) is to regulate bile flow and composition, in particular the hydration and alkalinity of the primary bile secreted by hepatocytes. After almost three decades of studies it is now become clear that cholangiocytes are also involved in epithelial innate immunity, in inflammation, and in the reparative processes in response to liver damage. An increasing number of evidence highlights the ability of cholangiocyte to undergo changes in phenotype and function in response to liver damage. By participating actively to the immune and inflammatory responses, cholangiocytes represent a first defense line against liver injury from different causes. Indeed, cholangiocytes express a number of receptors able to recognize pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), such as Toll-like receptors (TLR), which modulate their pro-inflammatory behavior. Cholangiocytes can be both the targets and the initiators of the inflammatory process. Derangements of the signals controlling these mechanisms are at the basis of the pathogenesis of different cholangiopathies, both hereditary and acquired, such as cystic fibrosis-related liver disease and sclerosing cholangitis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Mario Strazzabosco
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA; International Center for Digestive Health, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy.
| | - Romina Fiorotto
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA; International Center for Digestive Health, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy
| | - Massimiliano Cadamuro
- International Center for Digestive Health, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy
| | - Carlo Spirli
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA; International Center for Digestive Health, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy
| | - Valeria Mariotti
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Eleanna Kaffe
- Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
| | - Roberto Scirpo
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA
| | - Luca Fabris
- Digestive Disease Section, Yale University School of Medicine, New Haven, CT, USA; International Center for Digestive Health, Department of Surgery and Translational Medicine, University of Milan-Bicocca, Milan, Italy; Department of Molecular Medicine, University of Padova School of Medicine, Padova, Italy
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12
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Animal models of biliary injury and altered bile acid metabolism. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1254-1261. [PMID: 28709963 DOI: 10.1016/j.bbadis.2017.06.027] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 12/14/2022]
Abstract
In the last 25years, a number of animal models, mainly rodents, have been generated with the goal to mimic cholestatic liver injuries and, thus, to provide in vivo tools to investigate the mechanisms of biliary repair and, eventually, to test the efficacy of innovative treatments. Despite fundamental limitations applying to these models, such as the distinct immune system and the different metabolism regulating liver homeostasis in rodents when compared to humans, multiple approaches, such as surgery (bile duct ligation), chemical-induced (3,5-diethoxycarbonyl-1,4-dihydrocollidine, DDC, α-naphthylisothiocyanate, ANIT), viral infections (Rhesus rotavirustype A, RRV-A), and genetic manipulation (Mdr2, Cftr, Pkd1, Pkd2, Prkcsh, Sec63, Pkhd1) have been developed. Overall, they have led to a range of liver phenotypes recapitulating the main features of biliary injury and altered bile acid metabolisms, such as ductular reaction, peribiliary inflammation and fibrosis, obstructive cholestasis and biliary dysgenesis. Although with a limited translability to the human setting, these mouse models have provided us with the ability to probe over time the fundamental mechanisms promoting cholestatic disease progression. Moreover, recent studies from genetically engineered mice have unveiled 'core' pathways that make the cholangiocyte a pivotal player in liver repair. In this review, we will highlight the main phenotypic features, the more interesting peculiarities and the different drawbacks of these mouse models. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Fickert P. Bad memories from the gut may cause nightmares for the bile ducts. J Hepatol 2017; 66:5-7. [PMID: 27702642 DOI: 10.1016/j.jhep.2016.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 09/19/2016] [Indexed: 12/04/2022]
Affiliation(s)
- Peter Fickert
- Research Unit for Experimental and Molecular Hepatology, Medical University of Graz, Austria.
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Radosavljevic GD, Pantic J, Jovanovic I, Lukic ML, Arsenijevic N. The Two Faces of Galectin-3: Roles in Various Pathological Conditions. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2016. [DOI: 10.1515/sjecr-2016-0011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Galectin-3, a unique chimaera-type member of the lectin family, displays a wide range of activities. This versatile molecule is involved in fundamental biological processes, including cell proliferation, cell-cell adhesion, apoptosis and immune responses.
This review is aimed at providing a general overview of the biological actions and diverse effects of Galectin-3 in many pathological conditions, with a specific focus on autoimmunity, inflammation and tumour progression. We report herein that Galectin-3 exerts deleterious functions determined by promotion of tumour progression and liver inflammation or aggravation of T cell-mediated autoimmune diseases. On the other hand, Galectin-3 exhibits a protective role in metabolic abnormalities and primary biliary cirrhosis.
The paradoxical “yin and yang” functions of Galectin-3 depend not only on its tissue and cellular localization but also on its availability, glycosylation status and the expression level of its ligands.
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Affiliation(s)
- Gordana D. Radosavljevic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Jelena Pantic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Ivan Jovanovic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Miodrag L. Lukic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
| | - Nebojsa Arsenijevic
- Centre for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Serbia
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Adaptive immunity in the liver. Cell Mol Immunol 2016; 13:354-68. [PMID: 26996069 PMCID: PMC4856810 DOI: 10.1038/cmi.2016.4] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 01/06/2016] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.
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Deletion of Galectin-3 Enhances Xenobiotic Induced Murine Primary Biliary Cholangitis by Facilitating Apoptosis of BECs and Release of Autoantigens. Sci Rep 2016; 6:23348. [PMID: 26996208 PMCID: PMC4800400 DOI: 10.1038/srep23348] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 03/02/2016] [Indexed: 12/13/2022] Open
Abstract
Galectin-3 (Gal-3) is a carbohydrate binding lectin, with multiple roles in inflammatory diseases and autoimmunity including its antiapoptotic effect on epithelial cells. In particular, increased expression of Gal-3 in epithelial cells is protective from apoptosis. Based on the thesis that apoptosis of biliary epithelial cells (BECs) is critical to the pathogenesis of Primary Biliary Cholangitis (PBC), we have analyzed the role of Gal-3 in the murine model of autoimmune cholangitis. We took advantage of Gal-3 knockout mice and immunized them with a mimotope of the major mitochondrial autoantigen of PBC, 2-octynoic acid (2-OA) coupled to BSA (2OA-BSA) and evaluated the natural history of subsequent disease, compared to control wild-type mice, by measuring levels of antibodies to PDC-E2, immunohistology of liver, and expression of Gal-3. We report herein that deletion of Gal-3 significantly exacerbates autoimmune cholangitis in these mice. This is manifested by increased periportal infiltrations, bile duct damage, granulomas and fibrosis. Interestingly, the BECs of Gal-3 knockout mice had a higher response to apoptotic stimuli and there were more pro-inflammatory lymphocytes and dendritic cells (DCs) in the livers of Gal-3 knockout mice. In conclusion, Gal-3 plays a protective role in the pathways that lead to the inflammatory destruction of biliary epithelial cells.
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Yan C, Wang YH, Yu Q, Cheng XD, Zhang BB, Li B, Zhang B, Tang RX, Zheng KY. Clonorchis sinensis excretory/secretory products promote the secretion of TNF-alpha in the mouse intrahepatic biliary epithelial cells via Toll-like receptor 4. Parasit Vectors 2015; 8:559. [PMID: 26497121 PMCID: PMC4620022 DOI: 10.1186/s13071-015-1171-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 10/14/2015] [Indexed: 01/24/2023] Open
Abstract
Background Toll-like receptor 4 (TLR4), as one of the most important pathogen pattern recognitions (PPRs) plays a central role in elicitation of innate immunity and mediation of adaptive responses against foreign antigens. However, little is known of the roles of TLR4 in the immune responses of biliary epithelial cells (BECs) induced by Clonorchis sinensis, a parasite of significance in human health. Methods In the present study, the primary mouse intrahepatic biliary epithelial cells (MIBECs) were pre-treated with TLR4 inhibitor peptide or control peptide and then stimulated by excretory/secretory products (ESP) of C. sinensis, respectively. The expressions of TLR4 and relative cytokines were determined using western blot and a bead-based analytic detection system, respectively. Results The results showed that ESP of C. sinensis significantly increased the expression of TLR4 which promoted the expression of MyD88 and NF-κB in BECs; the levels of TNF-α but not IL-6 from MIBECs stimulated by ESP alone were also considerably increased, compared with the group of the medium stimulated. However, the concentration of TNF-α was significantly decreased when MIBECs were pre-treated with TLR4 inhibitor. In addition, ESP could depress the level of IL-6 in MIBECs which was elevated by LPS. Conclusions Our data for the first time demonstrate that ESP of C. sinensis can potently induce secretion of pro-inflammatory cytokines via TLR4 in MIBECs, which suggests that TLR4 plays an important role in host defenses against C. sinensis and the pathogenesis of clonorchiasis.
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Affiliation(s)
- Chao Yan
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Yan-Hong Wang
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Qian Yu
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Xiao-Dan Cheng
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Bei-Bei Zhang
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Bo Li
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Bo Zhang
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Ren-Xian Tang
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
| | - Kui-Yang Zheng
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou 221004, Jiangsu Province, People's Republic of China.
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Farina A, Delhaye M, Lescuyer P, Dumonceau JM. Bile proteome in health and disease. Compr Physiol 2014; 4:91-108. [PMID: 24692135 DOI: 10.1002/cphy.c130016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The study of bile proteins could improve the understanding of physiological processes involved in the regulation of the hepato-biliary system. Researchers have tried for years to investigate the bile proteome but, until recently, only a few tens of proteins were known. The advent of proteomics, availing of large-scale analytical devices paired with potent bioinformatic resources, lately allowed the identification of thousands of proteins in bile. Nevertheless, the knowledge of their role in the hepato-biliary system still represents almost a "blank page in the book of physiology." In this review, we first guide the reader through the historical phases of the analysis of bile protein content, emphasizing the recent progresses achieved through the use of proteomic techniques. Thereafter, we deeply explore the involvement of bile proteins in health and disease, with a particular focus on the discovery of biomarkers for biliary tract malignancies.
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Affiliation(s)
- Annarita Farina
- Biomedical Proteomics Research Group, Department of Human Protein Sciences, Geneva University, Geneva, Switzerland
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Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2013; 8:303-30. [PMID: 23347352 DOI: 10.1146/annurev-pathol-020712-164014] [Citation(s) in RCA: 225] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom
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High levels of FCγR3A and PRF1 expression in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. Dig Dis Sci 2013. [PMID: 23179144 DOI: 10.1007/s10620-012-2456-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Innate immunity plays an important role in the pathogenesis of primary biliary cirrhosis (PBC) that needs to be characterized. Levels and clinical relationship of Fc gamma receptor III-A (FcγR3A), tyrosine kinase binding protein (TYROBP) and perforin-1 (PRF1), important genes for nature killer (NK) cells, were analyzed in PBC patients. AIMS The purpose of this study was to explore the expression levels of the above-mentioned genes in peripheral blood mononuclear cells (PBMCs) from PBC patients. METHODS A total of 102 PBC patients and 85 healthy controls (HC) were recruited. The relative levels of FCγR3A, TYROBP, and PRF1 mRNA transcripts in PBMCs were determined by RT-PCR. The percentages of peripheral blood NK, natural killer T (NKT), FCγR3A(+) or PRF1(+) NK cells and PRF1(+) NKT cells in PBC patients and HC were also characterized by flow cytometry analysis. The potential associations of the percentages of NK and NKT cells with clinical indexes were analyzed. RESULTS The relative levels of FCγR3A, TYROBP, and PRF1 mRNA transcripts and the percentages of PRF1(+) NK and NKT cells in PBC patients were significantly higher than that in HC. Moreover, the percentages of PRF1-expressing NK and NKT cells in PBC patients were negatively associated with the levels of serum gamma-glutamyltransferase (GGT) and Mayo risk scores, and the relative levels of FCγR3A expression in NK cells of PBC patients were positively associated with the levels of serum GGT. CONCLUSIONS FCγR3A and PRF1 may participate in the pathogenesis and progression of PBC.
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Chen CC, Ho CY, Chaung HC, Tain YL, Hsieh CS, Kuo FY, Yang CY, Huang LT. Fish omega-3 fatty acids induce liver fibrosis in the treatment of bile duct-ligated rats. Dig Dis Sci 2013. [PMID: 23203732 DOI: 10.1007/s10620-012-2489-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Biliary atresia-induced cholestasis increases hepatic oxidative stress with eventual progression to cirrhosis and liver failure. Omega-3 fatty acids play a possible role in the regulation of oxidative stress and the improvement of cholestasis. AIM The goal of the present study is to investigate the role of dietary supplementation of fish omega-3 fatty acids in the reduction of hepatocellular damage by using a rat common bile duct ligation model. METHODS Sprague-Dawley rats received either sham or bile duct ligation (BDL) and were divided into four study groups: Sham+saline (Sham+sal) group, Sham+Fish oil (Sham+FO) group, BDL+saline (BDL+sal) group, and BDL+Fish oil (BDL+FO) group. Rats from each group were assigned to receive, besides regular chow, once daily with either normal saline or fish omega-3 fatty acids (0.4 % of its own body weight) via gavage for 10 days. Samples of blood, liver tissue homogenates, and histological studies from different groups were analyzed at the end of the study. RESULTS Rats from BDL+FO had significantly impaired liver function as compared to other study groups (p < 0.05 is of significant difference). Ishak scores and the TGF-b1 contents were significantly higher in rats that received BDL+FO, p < 0.05. Contrary to TGF-b1 liver content, rats from the BDL+FO group had the lowest glutathione levels among the study groups, p < 0.05. CONCLUSIONS Fish omega-3 fatty acids supplementation, albeit increased tissue content of DHA, tended to increase liver fibrosis in BDL rats, decrease liver glutathione level, and compromise hepatic function; fish oil supplementation to subjects with biliary atresia might be of potential hazard and should be used with caution.
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Affiliation(s)
- Chih-Cheng Chen
- Pediatrics Department, Kaohsiung Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, 123 Ta-Pei Road, Niao Song, Kaohsiung, 833, Taiwan
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Abstract
Cholangiocytes, or bile duct epithelia, were once thought to be the simple lining of the conduit system comprising the intra- and extrahepatic bile ducts. Growing experimental evidence demonstrated that cholangiocytes are in fact the first line of defense of the biliary system against foreign substances. Experimental advances in recent years have unveiled previously unknown roles of cholangiocytes in both innate and adaptive immune responses. Cholangiocytes can release inflammatory modulators in a regulated fashion. Moreover, they express specialized pattern-recognizing molecules that identify microbial components and activate intracellular signaling cascades leading to a variety of downstream responses. The cytokines secreted by cholangiocytes, in conjunction with the adhesion molecules expressed on their surface, play a role in recruitment, localization, and modulation of immune responses in the liver and biliary tract. Cholangiocyte survival and function is further modulated by cytokines and inflammatory mediators secreted by immune cells and cholangiocytes themselves. Because cholangiocytes act as professional APCs via expression of major histocompatibility complex antigens and secrete antimicrobial peptides in bile, their role in response to biliary infection is critical. Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis.
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Affiliation(s)
- Gaurav Syal
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Michel Fausther
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Jonathan A. Dranoff
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Barbhuiya MA, Sahasrabuddhe NA, Pinto SM, Muthusamy B, Singh TD, Nanjappa V, Keerthikumar S, Delanghe B, Harsha HC, Chaerkady R, Jalaj V, Gupta S, Shrivastav BR, Tiwari PK, Pandey A. Comprehensive proteomic analysis of human bile. Proteomics 2011; 11:4443-53. [PMID: 22114102 DOI: 10.1002/pmic.201100197] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 07/27/2011] [Accepted: 08/24/2011] [Indexed: 01/21/2023]
Abstract
Bile serves diverse functions from metabolism to transport. In addition to acids and salts, bile is composed of proteins secreted or shed by the hepatobiliary system. Although there have been previous efforts to catalog biliary proteins, an in-depth analysis of the bile proteome has not yet been reported. We carried out fractionation of non-cancerous bile samples using a multipronged approach (SDS-PAGE, SCX and OFFGEL) followed by MS analysis on an LTQ-Orbitrap Velos mass spectrometer using high resolution at both MS and MS/MS levels. We identified 2552 proteins - the largest number of proteins reported in human bile till date. To our knowledge, there are no previous studies employing high-resolution MS reporting a more detailed catalog of any body fluid proteome in a single study. We propose that extensive fractionation coupled to high-resolution MS can be used as a standard methodology for in-depth characterization of any body fluid. This catalog should serve as a baseline for the future studies aimed at discovering biomarkers from bile in gallbladder, hepatic, and biliary cancers.
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Affiliation(s)
- Mustafa A Barbhuiya
- Centre for Genomics, Molecular and Human Genetics, Jiwaji University, Gwalior, India
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Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice. Gastroenterology 2011; 141:1498-508, 1508.e1-5. [PMID: 21712022 PMCID: PMC3186841 DOI: 10.1053/j.gastro.2011.06.052] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 05/18/2011] [Accepted: 06/10/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) in the biliary epithelium reduces bile flow and alkalinization in patients with cystic fibrosis (CF). Liver damage is believed to result from ductal cholestasis, but only 30% of patients with CF develop liver defects, indicating that another factor is involved. We studied the effects of CFTR deficiency on Toll-like receptor 4 (TLR4)-mediated responses of the biliary epithelium to endotoxins. METHODS Dextran sodium sulfate (DSS) was used to induce colitis in C57BL/6J-Cftrtm1Unc (Cftr-KO) mice and their wild-type littermates. Ductular reaction and portal inflammation were quantified by keratin-19 and CD45 immunolabeling. Cholangiocytes isolated from wild-type and Cftr-KO mice were challenged with lipopolysaccharide (LPS); cytokine secretion was quantified. Activation of nuclear factor κB (NF-κB), phosphorylation of TLR4, and activity of Src were determined. HEK-293 that expressed the secreted alkaline phosphatase reporter and human TLR4 were transfected with CFTR complementary DNAs. RESULTS DSS-induced colitis caused biliary damage and portal inflammation only in Cftr-KO mice. Biliary damage and inflammation were not attenuated by restoring biliary secretion with 24-nor-ursodeoxycholic acid but were significantly reduced by oral neomycin and polymyxin B, indicating a pathogenetic role of gut-derived bacterial products. Cftr-KO cholangiocytes incubated with LPS secreted significantly higher levels of cytokines regulated by TLR4 and NF-κB. LPS-mediated activation of NF-κB was blocked by the TLR4 inhibitor TAK-242. TLR4 phosphorylation by Src was significantly increased in Cftr-KO cholangiocytes. Expression of wild-type CFTR in the HEK293 cells stimulated with LPS reduced activation of NF-κB. CONCLUSIONS CFTR deficiency alters the innate immunity of the biliary epithelium and reduces its tolerance to endotoxin, resulting in an Src-dependent inflammatory response mediated by TLR4 and NF-κB. These findings might be used to develop therapies for CF-associated cholangiopathy.
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Affiliation(s)
- Romina Fiorotto
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT, USA, Center for liver Research (CeliveR), and Division of Gastroenterology, Ospedali Riuniti Bergamo, Italy
| | - Roberto Scirpo
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT, USA, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milano, Italy
| | - Michael Trauner
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Luca Fabris
- Center for liver Research (CeliveR), and Division of Gastroenterology, Ospedali Riuniti Bergamo, Italy, Department of Medical and Surgical Sciences “P.G.Cevese,” Università di Padova, Padova, Italy
| | - Rafaz Hoque
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT, USA
| | - Carlo Spirli
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT, USA, Center for liver Research (CeliveR), and Division of Gastroenterology, Ospedali Riuniti Bergamo, Italy
| | - Mario Strazzabosco
- Dept. of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT, USA, Center for liver Research (CeliveR), and Division of Gastroenterology, Ospedali Riuniti Bergamo, Italy, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Milano, Italy
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Zhang X, Tian Y, Xu Z, Wang L, Hou C, Ling X. Healing Process of the Guinea Pig Common Bile Duct after End-to-End Anastomosis: Pathological Evaluation after 6 Months. Eur Surg Res 2011; 46:194-206. [DOI: 10.1159/000325451] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Accepted: 02/11/2011] [Indexed: 01/01/2023]
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Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 2010; 139:1481-96. [PMID: 20849855 DOI: 10.1053/j.gastro.2010.09.004] [Citation(s) in RCA: 208] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 09/01/2010] [Accepted: 09/07/2010] [Indexed: 12/11/2022]
Abstract
Cholestatic liver disorders are caused by genetic defects, mechanical aberrations, toxins, or dysregulations in the immune system that damage the bile ducts and cause accumulation of bile and liver tissue damage. They have common clinical manifestations and pathogenic features that include the responses of cholangiocytes and hepatocytes to injury. We review the features of bile acid transport, tissue repair and regulation, apoptosis, vascular supply, immune regulation, and cholangiocytes that are associated with cholestatic liver disorders. We now have a greater understanding of the physiology of cholangiocytes at the cellular and molecular levels, as well as genetic factors, repair pathways, and autoimmunity mechanisms involved in the pathogenesis of disease. These discoveries will hopefully lead to new therapeutic approaches for patients with cholestatic liver disease.
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Changho S, Ahmed AA. Neutrophils in biliary atresia. A study on their morphologic distribution and expression of CAP37. Pathol Res Pract 2010; 206:314-7. [DOI: 10.1016/j.prp.2010.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Revised: 01/21/2010] [Accepted: 02/02/2010] [Indexed: 01/30/2023]
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Hu G, Gong AY, Liu J, Zhou R, Deng C, Chen XM. miR-221 suppresses ICAM-1 translation and regulates interferon-gamma-induced ICAM-1 expression in human cholangiocytes. Am J Physiol Gastrointest Liver Physiol 2010; 298:G542-50. [PMID: 20110463 PMCID: PMC2853302 DOI: 10.1152/ajpgi.00490.2009] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Aberrant cholangiocyte reactions in response to inflammatory stimuli are important pathogenic factors for the persistent biliary inflammation in patients with cholangiopathies. Overexpression of intercellular cell adhesion molecule-1 (ICAM-1) in cholangiocytes is a common pathological feature in inflammatory cholangiopathies and can promote cholangiocyte interactions with effector lymphocytes in the portal region. In this study, we tested the involvement of miRNA-mediated posttranscriptional regulation in IFN-gamma-induced ICAM-1 expression in cholangiocytes. Using both immortalized and nonimmortalized human cholangiocyte cell lines, we found that IFN-gamma activated ICAM-1 transcription and increased ICAM-1 protein expression. Inhibition of ICAM-1 transcription could only partially block IFN-gamma-induced ICAM-1 expression at the protein level. In silico target prediction analysis revealed complementarity of miR-221 to the 3'-untranslated region of ICAM-1 mRNA. Targeting of ICAM-1 3'-untranslated region by miR-221 resulted in translational repression in cholangiocytes but not ICAM-1 mRNA degradation. Functional inhibition of miR-221 with anti-miR-221 induced ICAM-1 protein expression. Moreover, IFN-gamma stimulation decreased miR-221 expression in cholangiocytes in a signal transducer and activator of transcription 1-dependent manner. Transfection of miR-221 precursor abolished IFN-gamma-stimulated ICAM-1 protein expression. In addition, miR-221-mediated expression of ICAM-1 on cholangiocytes showed a significant influence on the adherence of cocultured T cells. These findings indicate that both transcriptional and miRNA-mediated posttranscriptional mechanisms are involved in IFN-gamma-induced ICAM-1 expression in human cholangiocytes, suggesting an important role for miRNAs in the regulation of cholangiocyte inflammatory responses.
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Affiliation(s)
- Guoku Hu
- Departments of 1Medical Microbiology and Immunology and
| | - Ai-Yu Gong
- Departments of 1Medical Microbiology and Immunology and
| | - Jun Liu
- Departments of 1Medical Microbiology and Immunology and
| | - Rui Zhou
- Departments of 1Medical Microbiology and Immunology and
| | - Caishu Deng
- 2Pathology, Creighton University Medical Center, Omaha, Nebraska
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