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Chi S, Rong L, Zhang M, Li Y, Zhou Y, Li X, Zhang X, Luo Z, Li S, Cao G, Tang ST. Biliary atresia: Rotavirus amplification of lipopolysaccharide/toll-like receptor 4 by mediating MMP7 upregulation through NF-κB. Pediatr Res 2025:10.1038/s41390-025-04128-4. [PMID: 40415071 DOI: 10.1038/s41390-025-04128-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Matrix metalloproteinase-7 (MMP7), which is expressed primarily by biliary epithelial cells (BECs), has been shown to promote biliary atresia (BA). However, the mechanism by which elevated MMP7 expression is induced in BA remains unclear. METHODS Mouse extrahepatic BECs were used to investigate MMP7 overexpression induced by rhesus rotavirus (RRV) and lipopolysaccharide (LPS). The cellular localization of TLR4 and related proteins in the liver specimens from model mice was analyzed by immunohistochemistry. In vivo experiments were performed in BA models with TLR4 inhibition or antibiotic treatment and their corresponding control groups. RESULTS RRV infection alone is insufficient to induce MMP7 expression in mouse extrahepatic BECs, whereas sequential RRV infection and low-dose LPS treatment could cause robust MMP7 overexpression. RRV disrupted BEC endotoxin tolerance via HMGB1-mediated TLR4 upregulation, which subsequently promoted NF-κB and MMP7 overexpression. BECs from experimental BA model mice presented significantly increased TLR4 expression and NF-κB activation. In vivo, treatment with TLR4 antibodies, inhibitors, or antibiotics reduced MMP7 production, alleviated disease severity, and improved survival rates in BA models. CONCLUSION RRV infection disrupts BEC tolerance to low-dose LPS, triggering TLR4/NF-κB-mediated MMP7 overexpression and hepatobiliary inflammation, advancing our understanding of the role of LPS/TLR4 signaling in BA pathogenesis. IMPACT STATEMENT Rhesus rotavirus infection induces the upregulation of TLR4 expression in BECs, disrupting their tolerance to physiological levels of LPS and resulting in robust activation of the NF-κB pathway and subsequent abundant expression of MMP7. In vivo inhibition of TLR4 or a reduction in LPS levels alleviates symptoms in newborn mice injected with RRV. This study underscores the crucial role of LPS/TLR4 pathway activation in the pathogenesis of biliary atresia, which may be a key potential therapeutic target.
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Affiliation(s)
- Shuiqing Chi
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liying Rong
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengxin Zhang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yibo Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Zhou
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangyang Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhibin Luo
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Li
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guoqing Cao
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shao-Tao Tang
- Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Li Y, Leung PS, Zhang W, Zhang S, Liu Z, Kurth M, Patterson AD, Gershwin ME, Song J. Immunobiology of bile and cholangiocytes. J Autoimmun 2025; 151:103376. [PMID: 39892203 DOI: 10.1016/j.jaut.2025.103376] [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: 12/18/2024] [Revised: 01/21/2025] [Accepted: 01/24/2025] [Indexed: 02/03/2025]
Abstract
The biliary tract is now recognized as an immune organ, and within the biliary tract, both bile and cholangiocytes play a key role in maintaining immune defense and homeostasis. First, immunoreactive proteins such as secretory IgA provide local antimicrobial effects. Second, bile acids (BAs) protect the biliary tree from immune-related injury through receptor signaling, mainly via the membrane-bound receptor TGR5 on cholangiocytes. Third, the biliary microbiota, similar to the intestinal microbiota, contributes to sustaining a stable physiobiological microenvironment. Fourth, cholangiocytes actively modulate the expression/release of adhesion molecules and cytokines/chemokines and are involved in antigen presentation; additionally, cholangiocyte senescence and apoptosis also influence immune responses. Conversely, aberrant bile composition, altered BA profiles, imbalances in the biliary microbiota, and cholangiocyte dysfunction are associated with immune-mediated cholangiopathies, including primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia. While current therapeutic agents that modulate BA homeostasis and receptor signaling have shown promise in preclinical and clinical studies, future research on biliary/intestinal microbiota and cholangiocyte function should focus on developing novel therapeutic strategies for treating cholangiopathies.
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Affiliation(s)
- Yang Li
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, PR China
| | - Patrick Sc Leung
- Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, 95616, USA
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, 95616, USA
| | - Shucheng Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, PR China
| | - Zhenning Liu
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, PR China
| | - Mark Kurth
- Department of Chemistry, University of California, Davis, CA, 95616, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, Pennsylvania State University, Pennsylvania, 16802, USA
| | - M Eric Gershwin
- Division of Rheumatology/Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, 95616, USA
| | - Junmin Song
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, PR China.
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Zhang J, Zao X, Zhang J, Guo Z, Jin Q, Chen G, Gan D, Du H, Ye Y. Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome? Int Immunopharmacol 2023; 115:109627. [PMID: 36577151 DOI: 10.1016/j.intimp.2022.109627] [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: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022]
Abstract
Cirrhosis is a progressive chronic liver disease caused by one or more causes and characterized by diffuse fibrosis, pseudolobules, and regenerated nodules. Once progression to hepatic decompensation, the function of the liver and other organs is impaired and almost impossible to reverse and recover, which often results in hospitalization, impaired quality of life, and high mortality. However, in the early stage of cirrhosis, there seems to be a possibility of cirrhosis reversal. The development of cirrhosis is related to the intestinal microbiota and activation of toll-like receptors (TLRs) pathways, which could regulate cell proliferation, apoptosis, expression of the hepatomitogen epiregulin, and liver inflammation. Targeting regulation of intestinal microbiota and TLRs pathways could affect the occurrence and development of cirrhosis and its complications. In this paper, we first reviewed the dynamic change of intestinal microbiota and TLRs during cirrhosis progression. And further discussed the interaction between them and potential therapeutic targets to reverse early staged cirrhosis.
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Affiliation(s)
- Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Ziwei Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da'nan Gan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China.
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Nguyen TH, Turek I, Meehan-Andrews T, Zacharias A, Irving HR. A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis. PLoS One 2022; 17:e0263968. [PMID: 35167625 PMCID: PMC8846508 DOI: 10.1371/journal.pone.0263968] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 02/01/2022] [Indexed: 12/27/2022] Open
Abstract
Background Interleukin-1 receptor associated kinase 3 (IRAK3) is a critical modulator of inflammation and is associated with endotoxin tolerance and sepsis. Although IRAK3 is known as a negative regulator of inflammation, several studies have reported opposing functions, and the temporal actions of IRAK3 on inflammation remain unclear. A systematic review and meta-analyses were performed to investigate IRAK3 expression and its effects on inflammatory markers (TNF-α and IL-6) after one- or two-challenge interventions, which mimic the hyperinflammatory and immunosuppression phases of sepsis, respectively, using human or animal in vivo models. Methods This systematic review and meta-analyses has been registered in the Open Science Framework (OSF) (Registration DOI: 10.17605/OSF.IO/V39UR). A systematic search was performed to identify in vivo studies reporting outcome measures of expression of IRAK3 and inflammatory markers. Meta-analyses were performed where sufficient data was available. Results The search identified 7778 studies for screening. After screening titles, abstracts and full texts, a total of 49 studies were included in the systematic review. The review identified significant increase of IRAK3 mRNA and protein expression at different times in humans compared to rodents following one-challenge, whereas the increases of IL-6 and TNF-α protein expression in humans were similar to rodent in vivo models. Meta-analyses confirmed the inhibitory effect of IRAK3 on TNF-α mRNA and protein expression after two challenges. Conclusions A negative correlation between IRAK3 and TNF-α expression in rodents following two challenges demonstrates the association of IRAK3 in the immunosuppression phase of sepsis. Species differences in underlying biology affect the translatability of immune responses of animal models to human, as shown by the dissimilarity in patterns of IRAK3 mRNA and protein expression between humans and rodents following one challenge that are further influenced by variations in experimental procedures.
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Affiliation(s)
- Trang H. Nguyen
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
- * E-mail: (HRI); (THN)
| | - Ilona Turek
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Terri Meehan-Andrews
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Anita Zacharias
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Helen R. Irving
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
- * E-mail: (HRI); (THN)
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Torre P, Motta BM, Sciorio R, Masarone M, Persico M. Inflammation and Fibrogenesis in MAFLD: Role of the Hepatic Immune System. Front Med (Lausanne) 2021; 8:781567. [PMID: 34957156 PMCID: PMC8695879 DOI: 10.3389/fmed.2021.781567] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
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Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Benedetta Maria Motta
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Baronissi, Italy
| | - Roberta Sciorio
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy
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Nguyen TH, Turek I, Meehan-Andrews T, Zacharias A, Irving H. Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis. PLoS One 2020; 15:e0244570. [PMID: 33382782 PMCID: PMC7774834 DOI: 10.1371/journal.pone.0244570] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 12/13/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND IRAK3 is a critical modulator of inflammation in innate immunity. IRAK3 is associated with many inflammatory diseases, including sepsis, and is required in endotoxin tolerance to maintain homeostasis of inflammation. The impact of IRAK3 on inflammatory markers such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cell culture models remains controversial. OBJECTIVE To analyse temporal effects of IRAK3 on inflammatory markers after one- or two-challenge interventions in cell culture models. METHODS A systematic search was performed to identify in vitro cell studies reporting outcome measures of expression of IRAK3 and inflammatory markers. Meta-analyses were performed where sufficient data were available. Comparisons of outcome measures were performed between different cell lines and human and mouse primary cells. RESULTS The literature search identified 7766 studies for screening. After screening titles, abstracts and full-texts, a total of 89 studies were included in the systematic review. CONCLUSIONS The review identifies significant effects of IRAK3 on decreasing NF-κB DNA binding activity in cell lines, TNF-α protein level at intermediate time intervals (4h-15h) in cell lines or at long term intervals (16h-48h) in mouse primary cells following one-challenge. The patterns of TNF-α protein expression in human cell lines and human primary cells in response to one-challenge are more similar than in mouse primary cells. Meta-analyses confirm a negative correlation between IRAK3 and inflammatory cytokine (IL-6 and TNF-α) expression after two-challenges.
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Affiliation(s)
- Trang Hong Nguyen
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Ilona Turek
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Terri Meehan-Andrews
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Anita Zacharias
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
| | - Helen Irving
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia
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Ronca V, Mancuso C, Milani C, Carbone M, Oo YH, Invernizzi P. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol 2020; 108:659-671. [PMID: 32349179 DOI: 10.1002/jlb.5mr0320-200r] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Clara Mancuso
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Ye Htun Oo
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Poblete JMS, Ballinger MN, Bao S, Alghothani M, Nevado JB, Eubank TD, Christman JW, Magalang UJ. Macrophage HIF-1α mediates obesity-related adipose tissue dysfunction via interleukin-1 receptor-associated kinase M. Am J Physiol Endocrinol Metab 2020; 318:E689-E700. [PMID: 32154744 PMCID: PMC7717118 DOI: 10.1152/ajpendo.00174.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hypoxia leading to stabilization of hypoxia-inducible factor 1α (HIF-1α) serves as an early upstream initiator for adipose tissue (AT) dysfunction. Monocyte-derived macrophage infiltration in AT contributes to inflammation, fibrosis and obesity-related metabolic dysfunction. It was previously reported that myeloid cell-specific deletion of Hif-1α protected against high-fat diet (HFD)-induced AT dysfunction. Prolyl hydroxylases (PHDs) are key regulators of HIF-1α. We examined the effects of myeloid cell-specific upregulation and stabilization of Hif-1α via deletion of prolyl-hydroxylase 2 (Phd2) and whether interleukin-1 receptor associated kinase-M (Irak-M), a known downstream target of Hif-1α, contributes to Hif-1α-induced AT dysfunction. Our data show that with HFD, Hif-1α and Irak-M expressions were increased in the AT macrophages of Phd2flox/flox/LysMcre mice compared with LysMcre mice. With HFD, Phd2flox/flox/LysMcre mice exhibited increased AT inflammation, fibrosis, and systemic insulin resistance compared with control mice. Furthermore, Phd2flox/flox/LysMcre mice bone marrow-derived macrophages exposed to hypoxia in vitro also had increased expressions of both Hif-1α and Irak-M. In wild-type mice, HFD induced upregulation of both HIF-1a and Irak-M in adipose tissue. Despite equivalent expression of Hif-1α compared with wild-type mice, globally-deficient Irak-M mice fed a HFD exhibited less macrophage infiltration, decreased inflammation and fibrosis and improved glucose tolerance. Global Irak-M deficiency was associated with an alternatively-activated macrophage phenotype in the AT after HFD. Together, these data show for the first time that an Irak-M-dependent mechanism likely mediates obesity-related AT dysfunction in conjunction with Hif-1α upregulation.
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Affiliation(s)
- Josept Mari S Poblete
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- College of Medicine, University of the Philippines Manila, Manila, Philippines
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Megan N Ballinger
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Shengying Bao
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Miriam Alghothani
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Jose B Nevado
- College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Timothy D Eubank
- Department of Microbiology, Immunology, & Cell Biology, West Virginia University, Morgantown, West Virginia
| | - John W Christman
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Ulysses J Magalang
- Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio
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Maroni L, Ninfole E, Pinto C, Benedetti A, Marzioni M. Gut-Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology. Cells 2020; 9:cells9030736. [PMID: 32192118 PMCID: PMC7140657 DOI: 10.3390/cells9030736] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/10/2020] [Accepted: 03/13/2020] [Indexed: 12/15/2022] Open
Abstract
The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut–liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.
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Affiliation(s)
- Luca Maroni
- Correspondence: ; Tel.: +39-071-220-6043; Fax: +39-071-220-6044
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Ortiz-Perez A, Donnelly B, Temple H, Tiao G, Bansal R, Mohanty SK. Innate Immunity and Pathogenesis of Biliary Atresia. Front Immunol 2020; 11:329. [PMID: 32161597 PMCID: PMC7052372 DOI: 10.3389/fimmu.2020.00329] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.
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Affiliation(s)
- Ana Ortiz-Perez
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Bryan Donnelly
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Haley Temple
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Greg Tiao
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, Netherlands
| | - Sujit Kumar Mohanty
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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11
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12
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Al-Shaghdali K, Durante B, Hayward C, Beal J, Foey A. Macrophage subsets exhibit distinct E. coli-LPS tolerisable cytokines associated with the negative regulators, IRAK-M and Tollip. PLoS One 2019; 14:e0214681. [PMID: 31120887 PMCID: PMC6533032 DOI: 10.1371/journal.pone.0214681] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 03/18/2019] [Indexed: 11/19/2022] Open
Abstract
Macrophages (Mϕs) play a central role in mucosal immunity by pathogen sensing and instruction of adaptive immune responses. Prior challenge to endotoxin can render Mφs refractory to secondary exposure, suppressing the inflammatory response. Previous studies demonstrated a differential subset-specific sensitivity to endotoxin tolerance (ET), mediated by LPS from the oral pathogen, Porphyromonas gingivalis (PG). The aim of this study was to investigate ET mechanisms associated with Mφ subsets responding to entropathogenic E. coli K12-LPS. M1- and M2-like Mφs were generated in vitro from the THP-1 cell line by differentiation with PMA and Vitamin D3, respectively. This study investigated ET mechanisms induced in M1 and M2 Mφ subsets, by measuring modulation of expression by RT-PCR, secretion of cytokines by sandwich ELISA, LPS receptor, TLR4, as well as endogenous TLR inhibitors, IRAK-M and Tollip by Western blotting. In contrast to PG-LPS tolerisation, E. coli K12-LPS induced ET failed to exhibit a subset-specific response with respect to the pro-inflammatory cytokine, TNFα, whereas exhibited a differential response for IL-10 and IL-6. TNFα expression and secretion was significantly suppressed in both M1- and M2-like Mφs. IL-10 and IL-6, on the other hand, were suppressed in M1s and refractory to suppression in M2s. ET suppressed TLR4 mRNA, but not TLR4 protein, yet induced differential augmentation of the negative regulatory molecules, Tollip in M1 and IRAK-M in M2 Mφs. In conclusion, E. coli K12-LPS differentially tolerises Mφ subsets at the level of anti-inflammatory cytokines, associated with a subset-specific divergence in negative regulators and independent of TLR4 down-regulation.
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Affiliation(s)
- Khalid Al-Shaghdali
- School of Biomedical Sciences, Faculty of Medicine & Dentistry, University of Plymouth, Drake Circus, Plymouth, United Kingdom
- College of Medicine, University of Hail, Hail, Kingdom of Saudi Arabia
| | - Barbara Durante
- School of Biomedical Sciences, Faculty of Medicine & Dentistry, University of Plymouth, Drake Circus, Plymouth, United Kingdom
| | - Christopher Hayward
- Department of Gastroenterology, Derriford Hospital, Plymouth, United Kingdom
| | - Jane Beal
- School of Biological and Marine Sciences, University of Plymouth, Drake Circus, Plymouth, United Kingdom
| | - Andrew Foey
- School of Biomedical Sciences, Faculty of Medicine & Dentistry, University of Plymouth, Drake Circus, Plymouth, United Kingdom
- * E-mail:
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13
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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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14
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Tang YM, Yu HY. Progress in research of mechanism of biliary epithelial cell injury in primary biliary cholangitis. Shijie Huaren Xiaohua Zazhi 2019; 27:36-42. [DOI: 10.11569/wcjd.v27.i1.36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic biliary cholestasis and progressive intrahepatic and small bile duct non- suppurative inflammation with early infiltration of inflammatory cells around biliary epithelial cells (BECs). BECs lining the bile duct express multiple receptors for pathogen-associated molecular patterns and can activate intracellular signaling pathways and participate in immune regulation. The etiology and pathogenesis of PBC are not fully understood yet, but the key step found in its pathogenesis is the targeted destruction of biliary cells. Since bile duct epithelial cells participate in a series of intrahepatic immune regulation processes, bile duct epithelial cell injury is an important mechanism involved in the development of intrahepatic inflammation in PBC. Therefore, understanding the mechanism of BEC injury can help us find some new targets for the treatment of PBC. This article briefly reviews the progress in the research of mechanism of biliary epithelial cell injury in PBC.
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Affiliation(s)
- Ying-Mei Tang
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
| | - Hai-Yan Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, Yunnan Province, China
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15
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Giordano DM, Pinto C, Maroni L, Benedetti A, Marzioni M. Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies. Int J Mol Sci 2018; 19:E3003. [PMID: 30275402 PMCID: PMC6213589 DOI: 10.3390/ijms19103003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/26/2018] [Accepted: 09/29/2018] [Indexed: 12/11/2022] Open
Abstract
Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.
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Affiliation(s)
- Debora Maria Giordano
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Claudio Pinto
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Antonio Benedetti
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
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16
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Cui Y, Jiang L, Xing R, Wang Z, Wang Z, Shao Y, Zhang W, Zhao X, Li C. Cloning, expression analysis and functional characterization of an interleukin-1 receptor-associated kinase 4 from Apostichopus japonicus. Mol Immunol 2018; 101:479-487. [DOI: 10.1016/j.molimm.2018.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 08/04/2018] [Accepted: 08/04/2018] [Indexed: 12/19/2022]
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17
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Rahtes A, Geng S, Lee C, Li L. Cellular and molecular mechanisms involved in the resolution of innate leukocyte inflammation. J Leukoc Biol 2018; 104:535-541. [PMID: 29688584 DOI: 10.1002/jlb.3ma0218-070r] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 12/14/2022] Open
Abstract
Inflammation is a host response to infection or damage and is vital for clearing pathogens and host debris. When this resolution fails to occur, chronic inflammation ensues. Chronic inflammation is typically characterized as a low-grade, persistent inflammatory process that can last for months or even years. This differs from acute inflammation, which is typically a fast, robust response to a stimulus followed by resolution with return to homeostasis. Inflammation resolution occurs through a variety of cellular processes and signaling components that act as "brakes" to keep inflammation in check. In cases of chronic inflammation, these "brakes" are often dysfunctional. Due to its prevalent association with chronic diseases, there is growing interest in characterizing these negative regulators and their cellular effects in innate leukocytes. In this review, we aim to describe key cellular and molecular homeostatic regulators of innate leukocytes, with particular attention to the emerging regulatory processes of autophagy and lysosomal fusion during inflammation resolution.
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Affiliation(s)
- Allison Rahtes
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA
| | - Shuo Geng
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA
| | - Christina Lee
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA
| | - Liwu Li
- Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia, USA
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18
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Harada K. Sclerosing and obstructive cholangiopathy in biliary atresia: mechanisms and association with biliary innate immunity. Pediatr Surg Int 2017; 33:1243-1248. [PMID: 29039048 DOI: 10.1007/s00383-017-4154-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2017] [Indexed: 12/13/2022]
Abstract
Biliary atresia (BA) is histologically characterized by a progressive, sclerosing cholangitis and the obstruction of extrahepatic bile ducts. In terms of the etiology and pathogenesis of BA, several viral infections consisting of dsRNA, including Reoviridae, have been implicated. Human biliary epithelial cells (BECs) possess an innate immune system consisting of Toll-like receptors (TLRs). BECs have negative regulatory mechanisms of TLR tolerance to avoid an excessive inflammatory response to lipopolysaccharide (LPS), a TLR4 ligand; however, they lack the tolerance to poly(I:C) (a synthetic analog of viral dsRNA), a TLR3 ligand. Treatment with poly(I:C) induces the expression of the apoptosis-inducer TNF-related apoptosis-inducing ligand (TRAIL), along with the antiviral molecule IFN-β1, and reduces the viability of BECs by enhancing apoptosis. In response, surviving BECs increase their expression of various markers, including basic FGF [an epithelial-mesenchymal transition (EMT)-inducer], S100A4 (a mesenchymal marker), and Snail (a transcriptional factor), and decrease that of epithelial markers such as CK19 and E-cadherin before undergoing EMT. Extrahepatic bile ducts in BA infants frequently show a lack of epithelial markers and an aberrant expression of vimentin, in addition to the enhancement of TRAIL and apoptosis. dsRNA viruses may directly induce apoptosis and EMT in human BECs as a result of the biliary innate immune response, supporting the notion that Reoviridae infections may be directly associated with the pathogenesis of cholangiopathies in BA.
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Affiliation(s)
- Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
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19
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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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20
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Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev 2017; 16:885-896. [PMID: 28698093 DOI: 10.1016/j.autrev.2017.07.002] [Citation(s) in RCA: 168] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 05/11/2017] [Indexed: 12/13/2022]
Abstract
Autoimmune cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acid transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses. However, progression of the disease may also affect the composition of gut microbiota, which in turn exacerbates the progression of cholestasis. In addition, the interaction between intestinal microbiota and bile acids is not unidirectional. Bile acids can shape the gut microbiota community, and in turn, intestinal microbes are able to alter bile acid pool. In general, gut microbiota actively communicates with bile acids, and together play an important role in the pathogenesis of PBC and PSC. Targeting the link between bile acids and intestinal microbiota offers exciting new perspectives for the treatment of those cholestatic liver diseases. This review highlights current understanding of the interactions between bile acids and intestinal microbiota and their roles in autoimmune cholestatic liver diseases. Further, we postulate a bile acids-intestinal microbiota-cholestasis triangle in the pathogenesis of autoimmune cholestatic liver diseases and potential therapeutic strategies by targeting this triangle.
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21
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Yin X, Gong X, Zhang L, Jiang R, Kuang G, Wang B, Chen X, Wan J. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d -galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M. Toxicol Appl Pharmacol 2017; 320:8-16. [DOI: 10.1016/j.taap.2017.02.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 02/07/2017] [Accepted: 02/13/2017] [Indexed: 12/22/2022]
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22
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Harada K. Immunopathology of Biliary Atresia. PATHOLOGY OF THE BILE DUCT 2017:121-137. [DOI: 10.1007/978-981-10-3500-5_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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23
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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: 125] [Impact Index Per Article: 13.9] [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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24
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The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis. Nat Commun 2016; 7:13436. [PMID: 27824038 PMCID: PMC5105176 DOI: 10.1038/ncomms13436] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 10/04/2016] [Indexed: 02/06/2023] Open
Abstract
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.
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25
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Chand HS, Mebratu YA, Montera M, Tesfaigzi Y. T cells suppress memory-dependent rapid mucous cell metaplasia in mouse airways. Respir Res 2016; 17:132. [PMID: 27765038 PMCID: PMC5073838 DOI: 10.1186/s12931-016-0446-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 10/05/2016] [Indexed: 12/19/2022] Open
Abstract
Background Airway epithelial cells (AECs) are crucial for mucosal and adaptive immunity but whether these cells respond in a memory-dependent manner is poorly studied. Previously, we have reported that LPS intratracheal instillation in rodents causes extensive neutrophilic inflammation and airway epithelial cell hyperplasia accompanied by mucous cell metaplasia (MCM). And the resolution process required a period of 40 d for the inflammation to subside and the lung epithelia to resemble the non-exposed condition. Therefore, the present study investigated the memory-dependent response of airway epithelial cells to a secondary LPS challenge after the initial inflammation was resolved. Methods Airway epithelial and mucous cells were assessed in response to a secondary LPS challenge in F344/N rats, and in C57BL/6 wild-type (Foxn1WT) and T cell-deficient athymic (Foxn1nu) mice that were instilled with LPS or saline 40 d earlier. Epithelial expression of TLR4, EGFR, and phosphorylated-ERK1/2 (pERK) were also analyzed. Results LPS-pretreated F344/N rats responded with elevated numbers of AECs after saline challenge and with 3-4-fold increased MCM following the LPS challenge in LPS- compared with saline-pretreated rats. LPS-pretreated rats showed 5-fold higher number of AECs expressing TLR4 apically than saline-pretreated rats. Also, the expression of EGFR was increased in LPS-pretreated rats along with the number of AECs with active or nuclear pERK, and the levels were further increased upon LPS challenge. LPS-pretreated Foxn1nu compared with Foxn1WT mice showed increased MCM and elevated levels of TLR4, EGFR, and nuclear pERK at 40 d after LPS instillation. LPS challenge further augmented MCM rapidly in Foxn1nu compared with Foxn1WT mice. Conclusion Together, these data suggest that AECs preserve an ‘innate memory’ that drives a rapid mucous phenotype via spatiotemporal regulation of TLR4 and EGFR. Further, T cells may suppress the sustained elevated expression of TLR4 and EGFR and thereby the hyperactive epithelial response. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0446-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hitendra S Chand
- COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, 87108, USA. .,Present Address: Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th St, Miami, FL, 33199, USA.
| | - Yohannes A Mebratu
- COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, 87108, USA
| | - Marena Montera
- COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, 87108, USA
| | - Yohannes Tesfaigzi
- COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, 87108, USA
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26
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Jin P, Bo L, Liu Y, Lu W, Lin S, Bian J, Deng X. Activator protein 1 promotes the transcriptional activation of IRAK-M. Biomed Pharmacother 2016; 83:1212-1219. [PMID: 27562721 DOI: 10.1016/j.biopha.2016.08.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/14/2016] [Accepted: 08/08/2016] [Indexed: 10/21/2022] Open
Abstract
Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator for Toll-like receptor signaling, which can regulate immune homeostasis and tolerance in a number of pathological settings. However, the mechanism for IRAK-M regulation at transcriptional level remains largely unknown. In this study, a 1.4kb upstream sequence starting from the major IRAK-M transcriptional start site was cloned into luciferase reporter vector pGL3-basic to construct the full-length IRAK-M promoter. Luciferase reporter plasmids harboring the full-length and the deletion mutants of IRAK-M were transfected into 293T and A549 cells, and their relative luciferase activity was measured. The results demonstrated that activator protein 1(AP-1) cis-element plays a crucial role in IRAK-M constitutive gene transcription. Silencing of c-Fos and/or c-Jun expression suppressed the IRAK-M promoter activity as well as its mRNA and protein expressions. As a specific inhibitor for AP-1 activation, SP600125 also significantly suppressed the basal transcriptional activity of IRAK-M, the binding activity of c-Fos/c-Jun with IRAK-M promoter, and IRAK-M protein expression. Taken together, the result of this study highlights the importance of AP-1 in IRAK-M transcription, which offers more information on the role of IRAK-M in infectious and non-infectious diseases.
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Affiliation(s)
- Peipei Jin
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Lulong Bo
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yongjian Liu
- College of Life Science, Nanjing University, Nanjing 210006, China
| | - Wenbin Lu
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Shengwei Lin
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jinjun Bian
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China; College of Life Science, Nanjing University, Nanjing 210006, China.
| | - Xiaoming Deng
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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Neagos J, Standiford TJ, Newstead MW, Zeng X, Huang SK, Ballinger MN. Epigenetic Regulation of Tolerance to Toll-Like Receptor Ligands in Alveolar Epithelial Cells. Am J Respir Cell Mol Biol 2016; 53:872-81. [PMID: 25965198 DOI: 10.1165/rcmb.2015-0057oc] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
To protect the host against exuberant inflammation and injury responses, cells have the ability to become hyporesponsive or "tolerized" to repeated stimulation by microbial and nonmicrobial insults. The lung airspace is constantly exposed to a variety of exogenous and endogenous Toll-like receptor (TLR) ligands, yet the ability of alveolar epithelial cells (AECs) to be tolerized has yet to be examined. We hypothesize that type II AECs will develop a tolerance phenotype upon repeated TLR agonist exposure. To test this hypothesis, primary AECs isolated from the lungs of mice and a murine AEC cell line (MLE-12) were stimulated with either a vehicle control or a TLR ligand for 18 hours, washed, then restimulated with either vehicle or TLR ligand for an additional 6 hours. Tolerance was assessed by measurement of TLR ligand-stimulated chemokine production (monocyte chemoattractant protein [MCP]-1/CCL2, keratinocyte chemoattractant [KC]/CXCL1, and macrophage inflammatory protein [MIP]-2/CXCL2). Sequential treatment of primary AECs or MLE-12 cells with TLR agonists resulted in induction of either tolerance or cross-tolerance. The induction of tolerance was not due to expression of specific negative regulators of TLR signaling (interleukin-1 receptor associated kinase [IRAK]-M, Toll-interacting protein [Tollip], single Ig IL-1-related receptor [SIGIRR], or suppressor of cytokine signaling [SOCS]), inhibitory microRNAs (miRs; specifically, miR-155 and miR146a), or secretion of inhibitory or regulatory soluble mediators (prostaglandin E2, IL-10, transforming growth factor-β, or IFN-α/β). Moreover, inhibition of histone demethylation or DNA methylation did not prevent the development of tolerance. However, treatment of AECs with the histone deacetylase inhibitors trichostatin A or suberoylanilide hyrozamine resulted in reversal of the tolerance phenotype. These findings indicate a novel mechanism by which epigenetic modification regulates the induction of tolerance in AECs.
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Affiliation(s)
- Jacqueline Neagos
- 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; and
| | - Theodore J Standiford
- 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; and
| | - Michael W Newstead
- 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; and
| | - Xianying Zeng
- 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; and
| | - Steven K Huang
- 1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; and
| | - Megan N Ballinger
- 2 Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University, Columbus, Ohio
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Yu Q, Li XY, Cheng XD, Shen LP, Fang F, Zhang B, Hua H, Yan C, Tang RX, Zheng KY. Expression and potential roles of IL-33/ST2 in the immune regulation during Clonorchis sinensis infection. Parasitol Res 2016; 115:2299-305. [PMID: 26944417 DOI: 10.1007/s00436-016-4974-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 02/22/2016] [Indexed: 12/17/2022]
Abstract
During clonorchiasis, immune responses of hosts are responsible for the removal of the worms and also are involved in the progress of the pathological damage caused by Clonorchis sinensis. Interleukin-33 (IL-33), a recently described cytokine signaling through the ST2 receptor, has emerged as a potent inducer to bile duct proliferation and fibrosis; however, little is known of this signaling in the pathogen-caused periductal inflammation and fibrosis. In the present study, using immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and flow cytometry, we studied the expression of IL-33/ST2 during C. sinensis infection, as well as their potential roles in C. sinensis-induced host immune responses. The results showed that a higher level of IL-33 was detected in the sera of patients of clonorchiasis (n = 45), compared with in those of healthy donors (n = 16). Similarly, in FVB mice experimentally infected with C. sinensis, a higher level of IL-33 was detected at latent stage both in the serum and in the liver, as well as the up-regulated expression of ST2 receptor on the inflammatory cells, especially on CD4(+) T cells in the liver of infected mice. Our results, for the first time, indicated that the increased IL-33/ST2 may be involved in the regulation of immunopathology induced by C. sinensis.
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Affiliation(s)
- 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
| | - Xiang-Yang Li
- 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
| | - Li-Ping Shen
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - Fan Fang
- 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
| | - Hui Hua
- Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, 221004, Jiangsu Province, People's Republic of China
| | - 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
| | - 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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Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015; 62:934-45. [PMID: 25435435 DOI: 10.1016/j.jhep.2014.11.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/08/2014] [Accepted: 11/16/2014] [Indexed: 12/16/2022]
Abstract
Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.
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Affiliation(s)
- Yasuni Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan; Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan.
| | - Motoko Sasaki
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
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Zhang Q, Yu H, Wu SD. Immune function of biliary epithelial cells. Shijie Huaren Xiaohua Zazhi 2015; 23:925-931. [DOI: 10.11569/wcjd.v23.i6.925] [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] [Indexed: 02/06/2023] Open
Abstract
Biliary epithelial cells (BECs) are the epithelial cells lining the bile duct, constituting the biliary system's first line of defense against pathogenic microorganisms. BECs can express many kinds of pathogen recognition receptors, activate intracellular signal transduction pathways, initiate the internal microbial defense system, including the release of pro-inflammatory cytokines and chemokines and antibacterial peptide synthesis, and maintain the integrity of the biliary epithelium. By expressing and releasing adhesion molecules and immune mediators, BECs interact with other cells in the liver, such as lymphocytes and Kupffer's cells. BECs are involved in a complex feedback mechanism of liver cells and thereby regulate the response to microbial infection. BECs actively participate in the biliary duct mucosal immunity and form an important component of liver immunity.
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Lee HJ, Kim KC, Han JA, Choi SS, Jung YJ. The early induction of suppressor of cytokine signaling 1 and the downregulation of toll-like receptors 7 and 9 induce tolerance in costimulated macrophages. Mol Cells 2015; 38:26-32. [PMID: 25518931 PMCID: PMC4314129 DOI: 10.14348/molcells.2015.2136] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 09/29/2014] [Accepted: 10/21/2014] [Indexed: 01/08/2023] Open
Abstract
Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88-dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-α and IL-6 through the delayed activation of the NF-κB pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-α secretion and restored NF-κB signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs.
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Affiliation(s)
- Hyo-Ji Lee
- BIT Medical Convergence Graduate Program, Kangwon National University, Chuncheon 200-701,
Korea
- Department of Biological Sciences, Kangwon National University, Chuncheon 200-701,
Korea
| | - Keun-Cheol Kim
- Department of Biological Sciences, Kangwon National University, Chuncheon 200-701,
Korea
| | - Jeong A Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kangwon National University, Chuncheon 200-701,
Korea
| | - Sun Shim Choi
- Department of Medical Biotechnology, Kangwon National University, Chuncheon 200-701,
Korea
| | - Yu-Jin Jung
- BIT Medical Convergence Graduate Program, Kangwon National University, Chuncheon 200-701,
Korea
- Department of Biological Sciences, Kangwon National University, Chuncheon 200-701,
Korea
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Ballinger MN, Newstead MW, Zeng X, Bhan U, Mo XM, Kunkel SL, Moore BB, Flavell R, Christman JW, Standiford TJ. IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury. THE JOURNAL OF IMMUNOLOGY 2015; 194:1894-904. [PMID: 25595781 DOI: 10.4049/jimmunol.1402377] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, TLR signaling has been identified as a regulator of pulmonary fibrosis. IL-1R-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M(-/-)) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of IL-13 compared with wild-type (WT) control mice. Bone marrow chimera experiments indicated that IRAK-M expression by bone marrow-derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M(-/-) macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M(-/-), mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis.
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Affiliation(s)
- Megan N Ballinger
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
| | - Michael W Newstead
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Xianying Zeng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Urvashi Bhan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Xiaokui M Mo
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH 43221
| | - Steven L Kunkel
- Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109; and
| | - Bethany B Moore
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
| | - Richard Flavell
- Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
| | - John W Christman
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210
| | - Theodore J Standiford
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109
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Abstract
Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC.
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Affiliation(s)
- Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
- Scott & White Digestive Disease Research Center, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
- Department of Medicine, Division Gastroenterology, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
- Scott & White Digestive Disease Research Center, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
- Department of Medicine, Division Gastroenterology, S and W and Texas A and M System Health Science Center, College of Medicine, Temple, Texas
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
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Sun Y, Li H, Sun MJ, Zheng YY, Gong DJ, Xu Y. Endotoxin Tolerance Induced by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli: Alternations in Toll-Like Receptor 2 and 4 Signaling Pathway. Inflammation 2013; 37:268-76. [DOI: 10.1007/s10753-013-9737-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Okamura A, Harada K, Nio M, Nakanuma Y. Interleukin-32 production associated with biliary innate immunity and proinflammatory cytokines contributes to the pathogenesis of cholangitis in biliary atresia. Clin Exp Immunol 2013; 173:268-75. [PMID: 23607494 DOI: 10.1111/cei.12103] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2013] [Indexed: 12/27/2022] Open
Abstract
Biliary atresia (BA) is thought to be associated with infections by viruses such as Reoviridae and is characterized histologically by fibrosclerosing cholangitis with proinflammatory cytokine-mediated inflammation. Interleukin (IL)-32 affects the continuous inflammation by increasing the production of proinflammatory cytokines. In this study, the role of IL-32 in the cholangitis of BA was examined. Immunohistochemistry for IL-32 and caspase 1 was performed using 21 samples of extrahepatic bile ducts resected from BA patients. Moreover, using cultured human biliary epithelial cells (BECs), the expression of IL-32 and its induction on stimulation with a Toll-like receptor [(TLR)-3 ligand (poly(I:C)] and proinflammatory cytokines was examined. BECs composing extrahepatic bile ducts showing cholangitis expressed IL-32 in BA, but not in controls. Caspase 1 was expressed constantly on BECs of both BA and control subjects. Furthermore, poly(I:C) and proinflammatory cytokines [(IL-1β, interferon (IFN)-γ and tumour necrosis factor (TNF)-α] induced IL-32 expression strongly in cultured BECs, accompanying the constant expression of TLR-3 and caspase 1. Our results imply that the expression of IL-32 in BECs was found in the damaged bile ducts of BA and induced by biliary innate immunity via TLR-3 and proinflammatory cytokines. These findings suggest that IL-32 is involved initially in the pathogenic mechanisms of cholangitis in BA and also plays an important role in the amplification and continuance of periductal inflammatory reactions. It is therefore tempting to speculate that inhibitors of IL-32 could be useful for attenuating cholangitis in BA.
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Affiliation(s)
- A Okamura
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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The immunophysiology and apoptosis of biliary epithelial cells: primary biliary cirrhosis and primary sclerosing cholangitis. Clin Rev Allergy Immunol 2013; 43:230-41. [PMID: 22689287 DOI: 10.1007/s12016-012-8324-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Biliary epithelial cells (BECs) provide the first line of defense against lumenal microbes in the biliary system. BECs express a variety of pathogen recognition receptors and can activate several intracellular signaling cascades to initiate antimicrobial defenses, including production of several anti-microbial peptides, cytokines, chemokines, and adhesion molecules. BECs also secrete immunoglobulin A and interact with other cells through expression and release of adhesion molecules and immune mediators. Recently, several reports suggest a correlation between apoptosis and autoimmunity through ineffective clearance of self-antigens. Primary biliary cirrhosis (PBC) is a slowly progressive, autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated destruction of BECs. We have demonstrated that the AMA self-antigen, namely the E2 subunit of the pyruvate dehydrogenase complex, is detectable in its antigenically reactive form within apoptotic blebs from human intrahepatic biliary epithelial cells and activates innate immune responses. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and the presence of concentric fibrosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis. However, apoptosis does not appear to play a central role in PSC. Despite both diseases involving immune-mediated injury to bile ducts, apoptosis occurs more commonly overall in PBC where it likely plays a unique role.
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Mitogen-activated protein kinase phosphatase 1 disrupts proinflammatory protein synthesis in endotoxin-adapted monocytes. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2013; 20:1396-404. [PMID: 23825193 DOI: 10.1128/cvi.00264-13] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Autotoxic production of proinflammatory mediators during early sepsis induces excessive inflammation, and their later suppression may limit the immune response. We previously reported that sepsis differentially represses transcription and translation of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to reprogram sepsis inflammation. This switch is gene specific and plays a crucial role in the clinically relevant syndrome of endotoxin adaptation/tolerance, multiorgan failure, and poor sepsis outcome. To further define the mechanisms responsible for translation disruption that follows inflammation induction, we used THP-1 human promonocytes as a model of Toll-like receptor 4 (TLR4) responses found in sepsis. We showed that phosphorylation-dependent activation of p38 mitogen-activated protein kinase (MAPK) and translation disruption of TNF-α and IL-6 follow increased MAPK phosphatase 1 (MKP-1) expression and that MKP-1 knockdown rephosphorylates p38 and restores the capacity to translate TNF-α and IL-6 mRNAs. We also observed that the RNA-binding protein motif 4 (RBM4), a p38 MAPK target, accumulates in an unphosphorylated form in the cytosol in endotoxin-adapted cells, suggesting that dephosphorylated RBM4 may function as a translational repressor. Moreover, MKP-1 knockdown promotes RBM4 phosphorylation, blocks its transfer from the nucleus to the cytosol, and reverses translation repression. We also found that microRNA 146a (miR-146a) knockdown prevents and miR-146a transfection induces MKP-1 expression, which lead to increases or decreases in TNF-α and IL-6 translation, respectively. We conclude that a TLR4-, miR-146a-, p38 MAPK-, and MKP-1-dependent autoregulatory pathway regulates the translation of proinflammatory genes during the acute inflammatory response by spatially and temporally modifying the phosphorylation state of RBM4 translational repressor protein.
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O’Hara SP, Tabibian JH, Splinter PL, LaRusso NF. The dynamic biliary epithelia: molecules, pathways, and disease. J Hepatol 2013; 58:575-582. [PMID: 23085249 PMCID: PMC3831345 DOI: 10.1016/j.jhep.2012.10.011] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Revised: 10/01/2012] [Accepted: 10/10/2012] [Indexed: 02/08/2023]
Abstract
Cholangiocytes, the cells lining bile ducts, are a heterogenous, highly dynamic population of epithelial cells. While these cells comprise a small fraction of the total cellular component of the liver, they perform the essential role of bile modification and transport of biliary and blood constituents. From a pathophysiological standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangiopathies. To date, the cause of most cholangiopathies remains obscure. It is known, however, that cholangiocytes exist in an environment rich in potential mediators of cellular injury, express receptors that recognize potential injurious insults, and participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, but are likely directly and actively involved in the pathogenesis of cholangiopathies. Here, we briefly summarize the characteristics of the reactive cholangiocyte and cholangiocyte responses to potentially injurious endogenous and exogenous molecules, and in addition, present emerging concepts in our understanding of the etiopathogenesis of several cholangiopathies.
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Affiliation(s)
- Steven P. O’Hara
- Department of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
| | - James H. Tabibian
- Department of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
| | - Patrick L. Splinter
- Department of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
| | - Nicholas F. LaRusso
- Department of Gastroenterology and Hepatology and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, United States
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Deng H, Maitra U, Morris M, Li L. Molecular mechanism responsible for the priming of macrophage activation. J Biol Chem 2013; 288:3897-906. [PMID: 23264622 PMCID: PMC3567643 DOI: 10.1074/jbc.m112.424390] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 12/10/2012] [Indexed: 12/13/2022] Open
Abstract
Host macrophages can be preprogrammed into opposing primed or tolerant states depending upon the nature and quantities of external stimulants. The paradigm of priming and tolerance has significant implications in the pathogenesis and resolution of both acute and chronic inflammatory diseases. However, the responsible mechanisms are not well understood. Here, we report that super low dose bacterial endotoxin lipopolysaccharide (LPS), as low as 5 pg/ml, primes the expression of proinflammatory mediators in macrophages upon a second high dose LPS challenge (100 ng/ml), although 5 pg/ml LPS itself does not trigger noticeable macrophage activation. Mice primed with super low dose LPS (0.5 μg/kg body weight) in vivo experience significantly elevated mortality following a second hit of high dose LPS as compared with saline-primed control mice. Mechanistically, we demonstrate that LPS primes macrophages by removing transcriptional suppressive RelB through interleukin receptor-associated kinase 1 and Tollip (Toll-interacting protein)-dependent mechanisms. This is in sharp contrast to the well documented RelB stabilization and induction by high dose LPS, potentially through the phosphoinositide 3-kinase (PI3K) pathway. Super low dose and high dose LPS cause opposing modulation of interleukin receptor-associated kinase 1 and PI3K pathways and lead to opposing regulation of RelB. The pathway switching induced by super low versus high dose LPS underscores the importance of competing intracellular circuitry during the establishment of macrophage priming and tolerance.
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Affiliation(s)
- Hui Deng
- From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910
| | - Urmila Maitra
- From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910
| | - Matt Morris
- From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910
| | - Liwu Li
- From the Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061-0910
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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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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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Benias PC, Gopal K, Bodenheimer H, Theise ND. Hepatic expression of toll-like receptors 3, 4, and 9 in primary biliary cirrhosis and chronic hepatitis C. Clin Res Hepatol Gastroenterol 2012; 36:448-54. [PMID: 23026026 DOI: 10.1016/j.clinre.2012.07.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Revised: 07/04/2012] [Accepted: 07/18/2012] [Indexed: 02/04/2023]
Abstract
UNLABELLED Toll-like receptors (TLRs) may play a role in the inflammatory patterns observed in primary biliary cirrhosis (PBC) and chronic hepatitis C (CHC). We investigated TLR 3, 4 and 9 expression in PBC and CHC using immunohistochemical staining. METHODS Patient biopsies of PBC (N=11) and CHC (N=15) were compared to disease free livers (n=7). The extent of TLR staining was assessed separately according to a semi-quantitative scale for hepatocytes, cholangiocytes and portal mononuclear cells (PMC). RESULTS In hepatocytes, TLR4 expression was increased (PBC; P=0.019), as was TLR9 (PBC; P=0.006, CHC; P=0.001). Cholangiocyte expression of TLRs 4 and 3 was reduced in both PBC (TLR4; P<0.0001, TLR3; P=0.006) and CHC (TLR4; P<0.0001, TLR3; P=0.014). Cholangiocyte expression of TLR9 was elevated for both groups and was significant in CHC (P=0.0115). PMCs showed up-regulation of TLR9 in PBC (P=0.022) and CHC (P=0.0001), with almost no expression of TLR 3 or 4. CONCLUSIONS In PBC and CHC, hepatocytes showed increased TLR 4 and 9 expression without change in TLR3. Cholangiocytes showed increased TLR9 expression as opposed to down-regulation of TLRs 3 and 4. PMCs in both diseases had significantly increased TLR 9 expression perhaps implicating TLR9 expression in chronic liver inflammation.
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Affiliation(s)
- Petros C Benias
- Beth Israel Medical Center, 16th Street at First Avenue, 17th Floor, Baird Hall, 10003 New York, USA.
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Ballinger MN, Newstead MW, Zeng X, Bhan U, Horowitz JC, Moore BB, Pinsky DJ, Flavell RA, Standiford TJ. TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death. THE JOURNAL OF IMMUNOLOGY 2012; 189:356-64. [PMID: 22661086 DOI: 10.4049/jimmunol.1103124] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling. Exposure of mice deficient in IRAK-M (IRAK-M(-/-)) to 95% oxygen resulted in reduced mortality compared with wild-type mice and occurred in association with decreased alveolar permeability and cell death. Using a bone marrow chimera model, we determined that IRAK-M's effects were mediated by structural cells rather than bone marrow-derived cells. We confirmed the expression of IRAK-M in alveolar epithelial cells (AECs) and showed that hyperoxia can induce the expression of this protein. In addition, IRAK-M(-/-) AECs exposed to hyperoxia experienced a decrease in cell death. IRAK-M may potentiate hyperoxic injury by suppression of key antioxidant pathways, because lungs and AECs isolated from IRAK-M(-/-) mice have increased expression/activity of heme oxygenase-1, a phase II antioxidant, and NF (erythroid-derived)-related factor-2, a transcription factor that initiates antioxidant generation. Treatment of IRAK-M(-/-) mice in vivo and IRAK-M(-/-) AECs in vitro with the heme oxygenase-1 inhibitor, tin protoporphyrin, substantially decreased survival and significantly reduced the number of live cells after hyperoxia exposure. Collectively, our data suggest that IRAK-M inhibits the induction of antioxidants essential for protecting the lungs against cell death, resulting in enhanced susceptibility to hyperoxic lung injury.
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Affiliation(s)
- Megan N Ballinger
- Division of Pulmonary and Critical Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Yang L, Seki E. Toll-like receptors in liver fibrosis: cellular crosstalk and mechanisms. Front Physiol 2012; 3:138. [PMID: 22661952 PMCID: PMC3357552 DOI: 10.3389/fphys.2012.00138] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2012] [Accepted: 04/24/2012] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that distinguish conserved microbial products, also known as pathogen-associated molecular patterns (PAMPs), from host molecules. Liver is the first filter organ between the gastrointestinal tracts and the rest of the body through portal circulation. Thus, the liver is a major organ that must deal with PAMPs and microorganisms translocated from the intestine and to respond to the damage associated molecular patterns (DAMPs) released from injured organs. These PAMPs and DAMPs preferentially activate TLR signaling on various cell types in the liver inducing the production of inflammatory and fibrogenic cytokines that initiate and prolong liver inflammation, thereby leading to fibrosis. We summarize recent findings on the role of TLRs, ligands, and intracellular signaling in the pathophysiology of liver fibrosis due to different etiology, as well as to highlight the potential role of TLR signaling in liver fibrosis associated with hepatitis C infection, non-alcoholic and alcoholic steatoheoatitis, primary biliary cirrhosis, and cystic fibrosis.
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Affiliation(s)
- Ling Yang
- Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine La Jolla, CA, USA
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Abstract
Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
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Mueller T, Beutler C, Picó AH, Shibolet O, Pratt DS, Pascher A, Neuhaus P, Wiedenmann B, Berg T, Podolsky DK. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int 2011; 31:1574-88. [PMID: 22093333 DOI: 10.1111/j.1478-3231.2011.02635.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 08/03/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND Pattern recognition receptors (PRRs) orchestrate the innate immune defence in human biliary epithelial cells (BECs). Tight control of PRR signalling provides tolerance to physiological amounts of intestinal endotoxins in human bile to avoid constant innate immune activation in BECs. AIMS We wanted to determine whether inappropriate innate immune responses to intestinal endotoxins contribute to the development and perpetuation of chronic biliary inflammation. METHODS We examined PRR-mediated innate immune responses and protective endotoxin tolerance in primary BECs isolated from patients with primary sclerosing cholangitis (PSC), alcoholic liver disease and patients without chronic liver disease. Expression studies comprised northern blots, RT-PCR, Western blots and immunocytochemistry. Functional studies comprised immuno-precipitation Western blots, FACS for endotoxin uptake, and NF-κB activation assays and ELISA for secreted IL-8 and tumour necrosis factor (TNF)-α. RESULTS Primary BECs from explanted PSC livers showed reversibly increased TLR and NOD protein expression and activation of the MyD88/IRAK signalling complex. Consecutively, PSC BECs exhibited inappropriate innate immune responses to endotoxins and did not develop immune tolerance after repeated endotoxin exposures. This endotoxin hyper-responsiveness was probably because of the stimulatory effect of abundantly expressed IFN-γ and TNF-α in PSC livers, which stimulated TLR4-mediated endotoxin signalling in BECs, leading to increased TLR4-mediated endotoxin incorporation and impaired inactivation of the TLR4 signalling cascade. As TNF-α inhibition partly restored protective innate immune tolerance, endogenous TNF-α secretion probably contributed to inappropriate endotoxin responses in BECs. CONCLUSION Inappropriate innate immune responses to intestinal endotoxins and subsequent endotoxin intolerance because of enhanced PRR signalling in BECs probably contribute to chronic cholangitis.
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Affiliation(s)
- Tobias Mueller
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
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Miranda-Díaz AG, Alonso-Martínez H, Hernández-Ojeda J, Arias-Carvajal O, Rodríguez-Carrizalez AD, Román-Pintos LM. Toll-like receptors in secondary obstructive cholangiopathy. Gastroenterol Res Pract 2011; 2011:265093. [PMID: 22114589 PMCID: PMC3205723 DOI: 10.1155/2011/265093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 08/16/2011] [Accepted: 08/22/2011] [Indexed: 12/19/2022] Open
Abstract
Secondary obstructive cholangiopathy is characterized by intra- or extrahepatic bile tract obstruction. Liver inflammation and structural alterations develop due to progressive bile stagnation. Most frequent etiologies are biliary atresia in children, and hepatolithiasis, postcholecystectomy bile duct injury, and biliary primary cirrhosis in adults, which causes chronic biliary cholangitis. Bile ectasia predisposes to multiple pathogens: viral infections in biliary atresia; Gram-positive and/or Gram-negative bacteria cholangitis found in hepatolithiasis and postcholecystectomy bile duct injury. Transmembrane toll-like receptors (TLRs) are activated by virus, bacteria, fungi, and parasite stimuli. Even though TLR-2 and TLR-4 are the most studied receptors related to liver infectious diseases, other TLRs play an important role in response to microorganism damage. Acquired immune response is not vertically transmitted and reflects the infectious diseases history of individuals; in contrast, innate immunity is based on antigen recognition by specific receptors designated as pattern recognition receptors and is transmitted vertically through the germ cells. Understanding the mechanisms for bile duct inflammation is essential for the future development of therapeutic alternatives in order to avoid immune-mediated destruction on secondary obstructive cholangiopathy. The role of TLRs in biliary atresia, hepatolithiasis, bile duct injury, and primary biliary cirrhosis is described in this paper.
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Affiliation(s)
- A. G. Miranda-Díaz
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - H. Alonso-Martínez
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - J. Hernández-Ojeda
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - O. Arias-Carvajal
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - A. D. Rodríguez-Carrizalez
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - L. M. Román-Pintos
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
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Marais M, Maloney SK, Gray DA. The development of endotoxin tolerance, and the role of hypothalamo-pituitary-adrenal function and glucocorticoids in Pekin ducks. J Exp Biol 2011; 214:3378-85. [DOI: 10.1242/jeb.056499] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
SUMMARY
Endotoxin tolerance represents a state of abated immunological responsiveness to pyrogens, which, in mammals, leads to the decline or abolition of the fever response. The development of endotoxin tolerance in birds is not well understood; consequently, the impact of repeated pathogenic exposure on the avian febrile response, and thus on the ability of birds to fight recurrent infection, is not known. We determined the effect of repeated injections of lipopolysaccharide (LPS) on the febrile response of Pekin ducks. We gave ducks five injections of LPS, spaced 1, 4 or 10 days apart, and recorded their core body temperature with abdominally implanted temperature data loggers. Once we established that Pekin ducks developed endotoxin tolerance, we investigated the effect of repeated injections of LPS on the central and peripheral segments of the hypothalamo-pituitary-adrenal (HPA) axis in an attempt to elucidate the role of glucocorticoids in the modulation of the febrile response during the tolerant period. When our ducks became tolerant to LPS, they had significantly higher basal levels of plasma corticosterone (CORT, the principal glucocorticoid in birds), and their HPA response to treatment with LPS was blunted. We propose that the augmented levels of basal plasma CORT resulted from sensitized HPA function, and this, in turn, contributed to the development of endotoxin tolerance. Regulation of the circulating level of CORT might be a possible target for the re-establishment of appropriate immune responses in birds.
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Affiliation(s)
- Manette Marais
- School of Physiology, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, South Africa
| | - Shane K. Maloney
- Physiology, School of Biomedical, Biomolecular, and Chemical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia
| | - David A. Gray
- School of Physiology, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, South Africa
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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: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [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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Wang SN, Wang ST, Lee KT. The potential interplay of adipokines with toll-like receptors in the development of hepatocellular carcinoma. Gastroenterol Res Pract 2011; 2011:215986. [PMID: 21960997 PMCID: PMC3179873 DOI: 10.1155/2011/215986] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 08/02/2011] [Accepted: 08/02/2011] [Indexed: 12/17/2022] Open
Abstract
Toll-like receptors (TLRs) are not only crucial to the initiation of the immune system, but also play a key role in several human inflammatory diseases. Hepatocellular carcinoma (HCC) is among those human cancers, which arise from sites of chronic inflammation. Therefore, a number of studies have explored the potential contribution of TLRs to HCC occurrence, which is initiated by exposure to chronic hepatic inflammation of different etiologies (including ethanol, and chronic B and C viral infections). Recent epidemiological data have shown the association of obesity and HCC development. Given the fact that adipose tissues can produce a variety of inflammation-related adipokines, obesity has been characterized as a state of chronic inflammation. Adipokines are therefore considered as important mediators linking inflammation to several metabolic diseases, including cancers. More recently, many experts have also shown the bridging role of TLRs between inflammation and metabolism. Hopefully, to retrieve the potential interaction between TLRs and adipokines in carcinogenesis of HCC will shed a new light on the therapeutic alternative for HCC. In this paper, the authors first review the respective roles of TLRs and adipokines, discuss their mutual interaction in chronic inflammation, and finally anticipate further investigations of this interaction in HCC development.
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Affiliation(s)
- Shen-Nien Wang
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Sen-Te Wang
- Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - King Teh Lee
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, No. 100, Shih-Chuan 1st Road, San Ming District, Kaohsiung 80756, Taiwan
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