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Labiano I, Agirre-Lizaso A, Olaizola P, Echebarria A, Huici-Izagirre M, Olaizola I, Esparza-Baquer A, Sharif O, Hijona E, Milkiewicz P, Milkiewicz M, González-Romero F, Aspichueta P, Monte MJ, Marin JJG, Vucur M, Luedde T, Marzioni M, Mann DA, Bujanda L, Rodrigues PM, Banales JM, Perugorria MJ. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation. J Hepatol 2022; 77:991-1004. [PMID: 35750136 DOI: 10.1016/j.jhep.2022.05.044] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 05/19/2022] [Accepted: 05/22/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis. METHODS TREM-2 expression was analyzed in the livers of patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Primary cultured Kupffer cells were incubated with lipopolysaccharide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed. RESULTS TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/- mice. This was characterized by enhanced necroptotic cell death, inflammatory responses and biliary expansion. Antibiotic treatment partially abrogated the effects observed in Trem-2-/- mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and dampened inflammatory gene transcription via a TREM-2-dependent mechanism. CONCLUSIONS TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic target. LAY SUMMARY Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (specifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.
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Affiliation(s)
- Ibone Labiano
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Aloña Agirre-Lizaso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Paula Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Anne Echebarria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Maider Huici-Izagirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Irene Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Aitor Esparza-Baquer
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
| | - Omar Sharif
- Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
| | - Elizabeth Hijona
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Nursing, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Donostia-San Sebastian, Spain
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Malgorzata Milkiewicz
- Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Francisco González-Romero
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain
| | - Patricia Aspichueta
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain; Biocruces Health Research Institute, Barakaldo, Spain
| | - Maria J Monte
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Jose J G Marin
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, Germany
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Derek A Mann
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey; Fibrofind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain.
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. HLA, gut microbiome and hepatic autoimmunity. Front Immunol 2022; 13:980768. [PMID: 36059527 PMCID: PMC9433828 DOI: 10.3389/fimmu.2022.980768] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022] Open
Abstract
Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele DRB1*03:01, possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in DRB1*03-negative patients, risk of AIH-1 is conferred by DRB1*04, which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with DRB1*07. The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the DRB1*13 in populations of Northern European ancestry. DRB1*1501 is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the DRB1*08 allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. DRB1*03:01 and B*08:01 confer susceptibility to primary sclerosing cholangitis (PSC), as well as DRB1*13 and DRB1*15 in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Faculty of Biomedical Sciences, Epatocentro Ticino and Università della Svizzera Italiana, Lugano, Switzerland
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
- *Correspondence: Benedetta Terziroli Beretta-Piccoli,
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
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Suriguga S, Li M, Luangmonkong T, Boersema M, de Jong KP, Oosterhuis D, Gorter AR, Beljaars L, Olinga P. Distinct responses between healthy and cirrhotic human livers upon lipopolysaccharide challenge: possible implications for acute-on-chronic liver failure. Am J Physiol Gastrointest Liver Physiol 2022; 323:G114-G125. [PMID: 35727919 DOI: 10.1152/ajpgi.00243.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure.
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Affiliation(s)
- Su Suriguga
- Key Laboratory of Clinical Diagnosis and Treatment Technology in Animal Disease, Ministry of Agriculture, College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, People's Republic of China.,Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Mei Li
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Theerut Luangmonkong
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands.,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Miriam Boersema
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Koert P de Jong
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Dorenda Oosterhuis
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - A R Gorter
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Leonie Beljaars
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, The Netherlands
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Wang C, Shi Y, Wang X, Ma H, Liu Q, Gao Y, Niu J. Peroxisome Proliferator-Activated Receptors Regulate Hepatic Immunity and Assist in the Treatment of Primary Biliary Cholangitis. Front Immunol 2022; 13:940688. [PMID: 35880178 PMCID: PMC9307989 DOI: 10.3389/fimmu.2022.940688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022] Open
Abstract
Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha, have received increasing attention in the treatment of primary biliary cholangitis. Reduced alkaline phosphatase levels and improved clinical outcomes were observed in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid (UDCA) monotherapy4 when treated with bezafibrate or fenofibrate combined with UDCA. In contrast to obeticholic acid, which exacerbates pruritus in patients, fibrates have been shown to relieve pruritus. Clinical trial outcomes show potential for the treatment of primary biliary cholangitis by targeting peroxisome proliferator-activated receptors. It is currently agreed that primary biliary cholangitis is an autoimmune-mediated cholestatic liver disease, and peroxisome proliferator-activated receptor is a nuclear receptor that regulates the functions of multiple immune cells, thus playing an important role in regulating innate and adaptive immunity. Therefore, this review focuses on the immune disorder of primary biliary cholangitis and summarizes the regulation of hepatic immunity when peroxisome proliferator-activated receptors are targeted for treating primary biliary cholangitis.
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Affiliation(s)
- Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Heming Ma
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Quan Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
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Fan Z, Pathak JL, Ge L. The Potential Role of RP105 in Regulation of Inflammation and Osteoclastogenesis During Inflammatory Diseases. Front Cell Dev Biol 2021; 9:713254. [PMID: 34414191 PMCID: PMC8369417 DOI: 10.3389/fcell.2021.713254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022] Open
Abstract
Inflammatory diseases have a negative impact on bone homeostasis via exacerbated local and systemic inflammation. Bone resorbing osteoclasts are mainly derived from hematopoietic precursors and bone marrow monocytes. Induced osteoclastogenesis during inflammation, autoimmunity, metabolic diseases, and cancers is associated with bone loss and osteoporosis. Proinflammatory cytokines, pathogen-associated molecular patterns, or endogenous pathogenic factors induce osteoclastogenic differentiation by binding to the Toll-like receptor (TLR) family expressed on surface of osteoclast precursors. As a non-canonical member of the TLRs, radioprotective 105 kDa (RP105 or CD180) and its ligand, myeloid differentiation protein 1 (MD1), are involved in several bone metabolic disorders. Reports from literature had demonstrated RP105 as an important activator of B cells, bone marrow monocytes, and macrophages, which regulates inflammatory cytokines release from immune cells. Reports from literature had shown the association between RP105 and other TLRs, and the downstream signaling mechanisms of RP105 with different “signaling-competent” partners in immune cells during different disease conditions. This review is focused to summarize: (1) the role of RP105 on immune cells’ function and inflammation regulation (2) the potential regulatory roles of RP105 in different disease-mediated osteoclast activation and the underlying mechanisms, and (3) the different “signaling-competent” partners of RP105 that regulates osteoclastogenesis.
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Affiliation(s)
- Zhou Fan
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Janak L Pathak
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Linhu Ge
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.,Institute of Oral Disease, Guangzhou Medical University, Guangzhou, China
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Xiang J, Yang G, Ma C, Wei L, Wu H, Zhang W, Tao X, Jiang L, Liang Z, Kang L, Yang S. Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ. Br J Pharmacol 2021; 178:2443-2460. [PMID: 33661551 DOI: 10.1111/bph.15429] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 02/07/2021] [Accepted: 02/21/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ. EXPERIMENTAL APPROACH Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ. KEY RESULTS Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ-deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked. CONCLUSION AND IMPLICATIONS In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.
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Affiliation(s)
- Jiaqing Xiang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Guangyan Yang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China
| | - Lingling Wei
- Institute of Agricultural Economics and Information, Jiangxi Academy of Agricultural Sciences, Jiangxi, China
| | - Han Wu
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Zhang
- State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China
| | - Xiuhua Tao
- Institute of Vegetables and Flowers, Jiangxi Academy of Agricultural Sciences, Jiangxi, China
| | - Lingyun Jiang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Zhen Liang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Lin Kang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Shu Yang
- Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China
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Bale S, Varga J, Bhattacharyya S. Role of RP105 and A20 in negative regulation of toll-like receptor activity in fibrosis: potential targets for therapeutic intervention. AIMS ALLERGY AND IMMUNOLOGY 2021. [DOI: 10.3934/allergy.2021009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Ma WT, Gao F, Gu K, Chen DK. The Role of Monocytes and Macrophages in Autoimmune Diseases: A Comprehensive Review. Front Immunol 2019; 10:1140. [PMID: 31178867 PMCID: PMC6543461 DOI: 10.3389/fimmu.2019.01140] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/07/2019] [Indexed: 12/19/2022] Open
Abstract
Monocytes (Mo) and macrophages (Mϕ) are key components of the innate immune system and are involved in regulation of the initiation, development, and resolution of many inflammatory disorders. In addition, these cells also play important immunoregulatory and tissue-repairing roles to decrease immune reactions and promote tissue regeneration. Several lines of evidence have suggested a causal link between the presence or activation of these cells and the development of autoimmune diseases. In addition, Mo or Mϕ infiltration in diseased tissues is a hallmark of several autoimmune diseases. However, the detailed contributions of these cells, whether they actually initiate disease or perpetuate disease progression, and whether their phenotype and functional alteration are merely epiphenomena are still unclear in many autoimmune diseases. Additionally, little is known about their heterogeneous populations in different autoimmune diseases. Elucidating the relevance of Mo and Mϕ in autoimmune diseases and the associated mechanisms could lead to the identification of more effective therapeutic strategies in the future.
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Affiliation(s)
- Wen-Tao Ma
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China.,School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Fei Gao
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Kui Gu
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - De-Kun Chen
- Veterinary Immunology Laboratory, College of Veterinary Medicine, Northwest A&F University, Yangling, China
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Immunological abnormalities in patients with primary biliary cholangitis. Clin Sci (Lond) 2019; 133:741-760. [DOI: 10.1042/cs20181123] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 02/28/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Abstract
Abstract
Primary biliary cholangitis (PBC), an autoimmune liver disease occurring predominantly in women, is characterized by high titers of serum anti-mitochondrial antibodies (AMAs) and progressive intrahepatic cholestasis. The immune system plays a critical role in PBC pathogenesis and a variety of immune cell subsets have been shown to infiltrate the portal tract areas of patients with PBC. Amongst the participating immune cells, CD4 T cells are important cytokine-producing cells that foster an inflammatory microenvironment. Specifically, these cells orchestrate activation of other immune cells, including autoreactive effector CD8 T cells that cause biliary epithelial cell (BEC) injury and B cells that produce large quantities of AMAs. Meanwhile, other immune cells, including dendritic cells (DCs), natural killer (NK) cells, NKT cells, monocytes, and macrophages are also important in PBC pathogenesis. Activation of these cells initiates and perpetuates bile duct damage in PBC patients, leading to intrahepatic cholestasis, hepatic damage, liver fibrosis, and eventually cirrhosis or even liver failure. Taken together, the body of accumulated clinical and experimental evidence has enhanced our understanding of the immunopathogenesis of PBC and suggests that immunotherapy may be a promising treatment option. Herein, we summarize current knowledge regarding immunological abnormalities of PBC patients, with emphasis on underlying pathogenic mechanisms. The differential immune response which occurs over decades of disease activity suggests that different therapies may be needed at different stages of disease.
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Czaja AJ. Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management. Dig Dis Sci 2018; 63:1706-1725. [PMID: 29671161 DOI: 10.1007/s10620-018-5072-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 04/12/2018] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis is a consequence of perturbations in homeostatic mechanisms that maintain self-tolerance but are incompletely understood. The goals of this review are to describe key pathogenic pathways that have been under-evaluated or unassessed in autoimmune hepatitis, describe insights that may shape future therapies, and encourage investigational efforts. The T cell immunoglobulin mucin proteins constitute a family that modulates immune tolerance by limiting the survival of immune effector cells, clearing apoptotic bodies, and expanding the population of granulocytic myeloid-derived suppressor cells. Galectins influence immune cell migration, activation, proliferation, and survival, and T cell exhaustion can be induced and exploited as a possible management strategy. The programmed cell death-1 protein and its ligands comprise an antigen-independent inhibitory axis that can limit the performance of activated T cells by altering their metabolism, and epigenetic changes can silence pro-inflammatory genes or de-repress anti-inflammatory genes that affect disease severity. Changes in the intestinal microbiota and permeability of the intestinal mucosal barrier can be causative or consequential events that affect the occurrence and phenotype of immune-mediated disease, and they may help explain the female propensity for autoimmune hepatitis. Perturbations within these homeostatic mechanisms have been implicated in experimental models and limited clinical experiences, and they have been favorably manipulated by monoclonal antibodies, recombinant molecules, pharmacological agents or dietary supplements. In conclusion, pathogenic mechanisms that have been implicated in other systemic immune-mediated and liver diseases but under-evaluated or unassessed in autoimmune hepatitis warrant consideration and rigorous evaluation.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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11
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Affiliation(s)
- Albert J. Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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12
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Hamidzadeh K, Christensen SM, Dalby E, Chandrasekaran P, Mosser DM. Macrophages and the Recovery from Acute and Chronic Inflammation. Annu Rev Physiol 2017; 79:567-592. [PMID: 27959619 PMCID: PMC5912892 DOI: 10.1146/annurev-physiol-022516-034348] [Citation(s) in RCA: 283] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals. The production of these cytokines can initiate a cascade of inflammatory mediator release that can lead to wholesale tissue destruction. The destructive inflammatory capability of macrophages is amplified by exposure to exogenous interferon-γ, which prolongs and heightens inflammatory responses. In simple terms, macrophages can thus be viewed as incendiary devices with hair triggers waiting to detonate. We have begun to ask questions about how these cells can be regulated to mitigate the collateral destruction associated with macrophage activation.
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Affiliation(s)
- Kajal Hamidzadeh
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742;
| | - Stephen M Christensen
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742;
| | - Elizabeth Dalby
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742;
| | - Prabha Chandrasekaran
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742;
| | - David M Mosser
- Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742;
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Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016; 8:1354-1369. [PMID: 27917262 PMCID: PMC5114472 DOI: 10.4254/wjh.v8.i32.1354] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/17/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
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Affiliation(s)
- Safak Kiziltas
- Safak Kiziltas, Department of Gastroenterology, Baskent University Istanbul Hospital, 34662 Istanbul, Turkey
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Czaja AJ. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroenterol 2016; 22:9257-9278. [PMID: 27895415 PMCID: PMC5107691 DOI: 10.3748/wjg.v22.i42.9257] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 10/07/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.
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15
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Han P, Sun D, Yang J. Interaction between periodontitis and liver diseases. Biomed Rep 2016; 5:267-276. [PMID: 27588170 PMCID: PMC4998044 DOI: 10.3892/br.2016.718] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/09/2016] [Indexed: 02/07/2023] Open
Abstract
Periodontitis is an oral disease that is highly prevalent worldwide, with a prevalence of 30–50% of the population in developed countries, but only ~10% present with severe forms. It is also estimated that periodontitis results in worldwide productivity losses amounting to ~54 billion USD yearly. In addition to the damage it causes to oral health, periodontitis also affects other types of disease. Numerous studies have confirmed the association between periodontitis and systemic diseases, such as diabetes, respiratory disease, osteoporosis and cardiovascular disease. Increasing evidence also indicated that periodontitis may participate in the progression of liver diseases, such as non-alcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma, as well as affecting liver transplantation. However, to the best of our knowledge, there are currently no reviews elaborating upon the possible links between periodontitis and liver diseases. Therefore, the current review summarizes the human trials and animal experiments that have been conducted to investigate the correlation between periodontitis and liver diseases. Furthermore, in the present review, certain mechanisms that have been postulated to be responsible for the role of periodontitis in liver diseases (such as bacteria, pro-inflammatory mediators and oxidative stress) are considered. The aim of the review is to introduce the hypothesis that periodontitis may be important in the progression of liver disease, thus providing dentists and physicians with an improved understanding of this issue.
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Affiliation(s)
- Pengyu Han
- The Liver Disease Diagnosis and Treatment Center of PLA, Bethune International Peace Hospital, Shijiazhuang, Hebei 050082, P.R. China
| | - Dianxing Sun
- The Liver Disease Diagnosis and Treatment Center of PLA, Bethune International Peace Hospital, Shijiazhuang, Hebei 050082, P.R. China
| | - Jie Yang
- Department of Public Healthcare, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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Li X, Yang J, Yang J, Dong W, Li S, Wu H, Li L. RP105 protects against myocardial ischemia–reperfusion injury via suppressing TLR4 signaling pathways in rat model. Exp Mol Pathol 2016; 100:281-6. [PMID: 26742900 DOI: 10.1016/j.yexmp.2015.12.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 12/21/2015] [Accepted: 12/23/2015] [Indexed: 12/22/2022]
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Koarada S, Tada Y. Roles of plasmablasts in IgG4-related disease and various immune-based diseases. World J Rheumatol 2016; 6:16-22. [DOI: 10.5499/wjr.v6.i1.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/23/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease with multiple organ disorders. Recently, in IgG4-RD, increased circulating plasmablasts have been found. The subsets of plasmablasts are negative for RP105 (CD180). A large population of B cells lacking RP105 (RP105-negative B cells) are found in patients with active with systemic lupus erythematosus and other systemic autoimmune diseases, including dermatomyositis, and Sjögren’s syndrome. In other conditions, such as neuromyelitis optica, Kawasaki’s disease, primary biliary cirrhosis and aging, RP105 expression on B cells and monocytes also alters. We review the basic science and clinical significance of RP105-negative B cells including plasmablasts in various immune-based diseases. RP105-negative B cells, especially plasmablasts, play crucial roles in both systemic and organ-specific autoimmune and inflammatory disorders.
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Chávez-Tapia NC, González-Rodríguez L, Jeong M, López-Ramírez Y, Barbero-Becerra V, Juárez-Hernández E, Romero-Flores JL, Arrese M, Méndez-Sánchez N, Uribe M. Current evidence on the use of probiotics in liver diseases. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.05.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Ma HD, Wang YH, Chang C, Gershwin ME, Lian ZX. The intestinal microbiota and microenvironment in liver. Autoimmun Rev 2014; 14:183-91. [PMID: 25315744 DOI: 10.1016/j.autrev.2014.10.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 10/05/2014] [Indexed: 12/12/2022]
Abstract
The intestinal microbiome plays a significant role in the development of autoimmune diseases, in particular, inflammatory bowel diseases. But the interplay between the intestinal tract and the liver may explain the increased association with autoimmune liver diseases and inflammatory bowel diseases. The gut-liver axis involves multiple inflammatory cell types and cytokines, chemokines and other molecules which lead to the destruction of normal liver architecture. Triggers for the initiation of these events are unclear, but appear to include multiple environmental factors, including pathogenic or even commensal microbial agents. The variation in the gut microbiome has been cited as a major factor in the pathogenesis of autoimmune liver disease and even other autoimmune diseases. The unique positioning of the liver at the juncture of the peripheral circulation and the portal circulation augments the interaction between naïve T cells and other hepatic cells and leads to the disruption in the development of tolerance to commensal bacteria and other environmental agents. Finally, the innate immune system and in particular toll-like receptors play a significant role in the pathogenesis of autoimmune liver disease.
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Affiliation(s)
- Hong-Di Ma
- Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Yin-Hu Wang
- Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, USA.
| | - Zhe-Xiong Lian
- Liver Immunology Laboratory, Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China; Innovation Center for Cell Biology, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui 230027, China.
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20
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The role of vitamin d in primary biliary cirrhosis: possible genetic and cell signaling mechanisms. Gastroenterol Res Pract 2013; 2013:602321. [PMID: 23589715 PMCID: PMC3622384 DOI: 10.1155/2013/602321] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 11/08/2012] [Accepted: 11/12/2012] [Indexed: 02/08/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an immune-mediated chronic inflammatory disease of the liver of unknown etiology. Vitamin D deficiency is highly prevalent in patients with PBC, and many studies have demonstrated the significant effect of calcitriol on liver cell physiology. Vitamin D has antiproliferative and antifibrotic effects on liver fibrosis. Genetic studies have provided an opportunity to determine which proteins link vitamin D to PBC pathology (e.g., the major histocompatibility complex class II molecules, the vitamin D receptor, toll-like receptors, apolipoprotein E, Nramp1, and cytotoxic T lymphocyte antigen-4). Vitamin D also exerts its effect on PBC through cell signaling mechanisms, that is, matrix metalloproteinases, prostaglandins, reactive oxygen species, and the transforming growth factor betas. In conclusion, vitamin D may have a beneficial role in the treatment of PBC. The best form of vitamin D for use in the PBC is calcitriol because it is the active form of vitamin D3 metabolite, and its receptors are present in the sinusoidal endothelial cells, Kupffer cells, and stellate cells of normal livers, as well as in the biliary cell line.
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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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Liang S, Webb T, Li Z. Role of gut microbiota in liver diseases. Hepatol Res 2013; 43:139-46. [PMID: 22970713 PMCID: PMC3894231 DOI: 10.1111/j.1872-034x.2012.01088.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/24/2012] [Accepted: 08/15/2012] [Indexed: 12/19/2022]
Abstract
The liver constantly encounters food-derived antigens and bacterial components such as lipopolysaccharide translocated from the gut into the portal vein. Bacterial components stimulate Toll-like receptors (TLR), which are expressed on Kupffer cells, biliary epithelial cells, hepatocytes, hepatic stellate cells, endothelial cells and dendritic cells and recognize specific pathogen-associated molecular patterns. The signaling of TLR to its main ligand triggers inflammation. Usually, in order to protect against hyperactivation of the immune system and to prevent organ failure by persistent inflammation, TLR tolerance to repeated stimuli is induced. In chronic liver diseases, a breakdown in TLR tolerance occurs. Furthermore, Kupffer cells, hepatic stellate cells and natural killer T cells are key components of innate immunity. Decreased numbers and impaired ability of these cells lead to failures in immune tolerance, resulting in persistent inflammation. Recently, the activation of inflammasome was revealed to control the secretion of pro-inflammatory cytokines such as interleukin-1β in response to bacterial pathogens. Innate immunity seems to be an important contributor to the pathogenesis of fatty liver disease and autoimmune liver disease. Recently, probiotics were reported to affect various liver diseases via shifts in gut microbiota and the stability of intestinal permeability. However, many unresolved questions remain. Further analysis will be needed to gain a more comprehensive understanding of the association of innate immunity with the pathogenesis of various liver diseases.
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Affiliation(s)
- Shuwen Liang
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21205
| | - Tonya Webb
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Zhiping Li
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21205
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Shi TY, Zhang FC. Role of autoimmunity in primary biliary cirrhosis. World J Gastroenterol 2012; 18:7141-8. [PMID: 23326118 PMCID: PMC3544015 DOI: 10.3748/wjg.v18.i48.7141] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Revised: 07/16/2012] [Accepted: 08/14/2012] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis. The pathogenesis of PBC involves environmental factors, genetic predisposition and loss of immune tolerance. In recent years, it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC. In this study, the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.
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Abstract
TLRs (Toll-like receptors), as evolutionarily conserved germline-encoded pattern recognition receptors, have a crucial role in early host defence by recognizing so-called PAMPs (pathogen-associated molecular patterns) and may serve as an important link between innate and adaptive immunity. In the liver, TLRs play an important role in the wound healing and regeneration processes, but they are also involved in the pathogenesis and progression of various inflammatory liver diseases, including autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, fibrogenesis, and chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection. Hepatitis viruses have developed different evading strategies to subvert the innate immune system. Thus recent studies have suggested that TLR-based therapies may represent a promising approach in the treatment in viral hepatitis. The present review focuses on the role of the local innate immune system, and TLRs in particular, in the liver.
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Broering R, Montag M, Jiang M, Lu M, Sowa JP, Kleinehr K, Gerken G, Schlaak JF. Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state. Int Immunol 2011; 23:537-44. [PMID: 21750146 DOI: 10.1093/intimm/dxr048] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Only little is known about the mechanisms of action of corticosteroids in the treatment of inflammatory liver diseases. As there is increasing evidence that stimulation of the innate immune system plays an important pathogenetic role in these conditions, we hypothesized that steroids may interfere with the activation of the Toll-like receptor (TLR) system of the liver. METHODS To test this hypothesis, murine non-parenchymal liver cells (Kupffer cells, liver sinusoidal endothelial cells) and primary hepatocytes were stimulated with TLR 1-9 ligands in the presence or absence of dexamethasone. Expression of pro- and anti-inflammatory cytokines was determined by quantitative reverse transcription-PCR or ELISA, respectively. Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) activation was assessed by western blot analysis. RESULTS TLR agonists induced the expression of pro- [tumor necrosis factor-α (TNF-α), IL-6, IL-1β, IFN-β] and anti-inflammatory cytokines [IL-10, transforming growth factor-β (TGF-β)], which was differentially modulated by steroid treatment. TNF-α and IL-6 expression was suppressed by dexamethasone, while IL-10 but not TGF-β was enhanced after TLR stimulation. IFN-β production induced by TLR 4 agonists but not TLR 3 agonists was inhibited by dexamethasone. TLR expression itself was down-regulated by steroid treatment in a cell type-specific manner. These effects were associated with suppression of the TLR-mediated activation of NF-κB. CONCLUSIONS TLR signaling is modulated by corticosteroids in a cell type-specific fashion resulting in down-regulation of TLR expression, suppression of pro-inflammatory and up-regulation of anti-inflammatory cytokines. This represents an as yet unknown mechanism of action for corticosteroids that may at least in part explain their therapeutic effects in inflammatory liver diseases.
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Affiliation(s)
- Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital of Essen, Germany
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Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R, Dinis-Ribeiro M, Leite-Moreira AF. Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 2010; 14:347-68. [PMID: 20146632 DOI: 10.1517/14728221003642027] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Toll-like receptors (TLRs) are innate immunity receptors that recognize several different antigens, initiating immunological/inflammatory responses. Recent evidence associates numerous pathophysiological processes and diseases with dysregulated activation of these receptors, conferring a potential therapeutic value to their modulation. AREAS COVERED IN THIS REVIEW The aim of this systematic review that covers literature from the past 10 years is to address the role of TLRs in the pathophysiology of gastrointestinal (GI) diseases as well as the therapeutic potential of modulating TLRs' signaling pathways in GI pathology. WHAT THE READER WILL GAIN This review shows that TLRs play an important role in the pathophysiology of several GI diseases and that modulating TLRs signaling pathways may have an enormous therapeutic potential. Different methods for modulation of TLRs' activity in GI tract, with direct agonists/antagonists but also with non-specific substances, like antibiotics or probiotics, are presented. TAKE HOME MESSAGE Even though TLRs modulators have been used for therapy in some GI diseases, further research, particularly in humans, is needed in order to establish the precise role of the different TLRs in the diverse GI diseases and to motivate clinical trials that consider TLRs as therapeutic targets in GI pathology.
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Affiliation(s)
- Pedro Pimentel-Nunes
- Department of Physiology, Cardiovascular Research & Development Unit, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319, Portugal.
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Abstract
The innate immune response to invading pathogens is centred upon a family of non-clonal, germline-encoded pattern recognition receptors (PRRs), the Toll-like receptors (TLRs). These provide specificity for a vast range of microbial pathogens, and offer an immediate anti-microbial response system. Thirteen mammalian TLRs have been described; 10 are expressed in humans, each responsible for the recognition of distinct, invariant microbial structures originating from bacteria, viruses, fungi and protozoa. The two most thoroughly studied are TLR4 and TLR2, the PRRs for Gram-negative and Gram-positive bacterial products, respectively. TLR4 is also the major receptor recognising endogenous ligands released from damaged or dying cells. Activation of a TLR by its relevant ligand rapidly ignites a complex intracellular signaling cascade that ultimately results in upregulation of inflammatory genes and production of proinflammatory cytokines, interferons and recruitment of myeloid cells. It also stimulates expression, upon antigen presenting cells, of co-stimulatory molecules required to induce an adaptive immune response. Whilst a robust TLR response is critical for survival and defence against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental. Such 'unhelpful TLR responses' could form the basis for a large number of gastrointestinal and liver disorders, including inflammatory bowel disease, viral hepatitis, autoimmune liver diseases and hepatic fibrosis. As our understanding of TLRs expands, the pathogenesis of a number of gastrointestinal disorders will be further elucidated, and this offers potential for specific therapies aimed directly at TLR signaling.
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Affiliation(s)
- Adam G Testro
- Innate Immunity Laboratory, Department of Medicine, Monash University, Monash, Australia.
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28
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Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns and signal through adaptor molecules, myeloid differentiation factor 88 (MyD88), Toll/IL-1 receptor domain containing adaptor protein (TIRAP), Toll/IL-1 receptor domain containing adaptor inducing interferon-beta (TRIF), and TRIF-related adaptor molecule (TRAM) to activate transcription factors, nuclear factor (NF)-kappaB, activator protein 1 (AP-1), and interferon regulatory factors (IRFs) leading to the initiation of innate immunity. This system promptly initiates host defenses against invading microorganisms. Endogenous TLR ligands such as the products from dying cells may also engage with TLRs as damage-associated molecular patterns. Although Kupffer cells are considered the primary cells to respond to pathogen associated molecular patterns in the liver, recent studies provide evidence of TLR signaling in hepatic nonimmune cell populations, including hepatocytes, biliary epithelial cells, endothelial cells, and hepatic stellate cells. This review highlights advances in TLR signaling in the liver, the role of TLRs in the individual hepatic cell populations, and the implication of TLR signaling in acute and chronic liver diseases. We further discuss recent advances regarding cytosolic pattern recognition receptors, RNA helicases that represents a new concept in chronic hepatitis C virus infection.
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Affiliation(s)
- Ekihiro Seki
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
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