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1
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Rieder F, Nagy LE, Maher TM, Distler JHW, Kramann R, Hinz B, Prunotto M. Fibrosis: cross-organ biology and pathways to development of innovative drugs. Nat Rev Drug Discov 2025:10.1038/s41573-025-01158-9. [PMID: 40102636 DOI: 10.1038/s41573-025-01158-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 03/20/2025]
Abstract
Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.
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Affiliation(s)
- Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.
- Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA.
| | - Laura E Nagy
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Toby M Maher
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- National Heart and Lung Institute, Imperial College, London, UK
| | - Jörg H W Distler
- Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
- Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Rafael Kramann
- Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Marco Prunotto
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
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2
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Su T, He Y, Wang M, Zhou H, Huang Y, Ye M, Guo Q, Xiao Y, Cai G, Zhao M, Wang J, Luo X. Macrophage-Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406500. [PMID: 39279458 PMCID: PMC11558151 DOI: 10.1002/advs.202406500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/16/2024] [Indexed: 09/18/2024]
Abstract
The dynamic interplay between parenchymal hepatocytes and non-parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (MASH), the molecular underpinnings of MASH progression remain poorly understood, and therapies to arrest MASH progression remain elusive. Herein, it is revealed that the expression of grancalcin (GCA) is upregulated in the macrophages of patients and rodents with MASH and correlates with MASH progression. Notably, the administration of recombinant GCA aggravates the development of MASH, whereas, Gca deletion in myeloid cells blunts liver steatosis and inflammation in multiple MASH murine models. Mechanistically, GCA activates macrophages via TLR9-NF-κB signaling, and the activated macrophages promote hepatocyte lipid accumulation and apoptosis via secretion of Interleukin-6(IL-6), Tumor Necrosis Factor α (TNFα), and Interleukin-1β(IL-1β), thereby leading to hepatic steatosis and inflammation. Finally, the therapeutic administration of antibody blocking GCA effectively halts the progression of MASH. Collectively, these findings implicate GCA as a crucial mediator of MASH and clarify a new metabolic signaling axis between the hepatocytes and macrophages, implying that GCA can emerge as a particularly interesting putative therapeutic target for reversing MASH progression.
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Affiliation(s)
- Tian Su
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Yue He
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Min Wang
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Haiyan Zhou
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Yan Huang
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Mingsheng Ye
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Qi Guo
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Ye Xiao
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Guangping Cai
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Mingyang Zhao
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
| | - Jianping Wang
- Department of EndocrinologyThe Second Affiliated Hospital of University of South ChinaHengyangHunan421000China
| | - Xianghang Luo
- Department of EndocrinologyEndocrinology Research CenterXiangya Hospital of Central South UniversityChangshaHunan410008China
- National Clinical Research Center for Geriatric DisordersXiangya HospitalChangshaHunan410008China
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Hatten H, Colyn L, Volkert I, Gaßler N, Lammers T, Hofmann U, Hengstler JG, Schneider KM, Trautwein C. Loss of Toll-like receptor 9 protects from hepatocellular carcinoma in murine models of chronic liver disease. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167321. [PMID: 38943920 DOI: 10.1016/j.bbadis.2024.167321] [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: 03/21/2024] [Revised: 06/19/2024] [Accepted: 06/20/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND & AIMS Toll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important modulator of innate immunity. Here we investigated the role of Tlr9 in fibrogenesis and progression of hepatocellular carcinoma in chronic liver disease. MATERIALS AND METHODS We treated mice with a constitutive deletion of Tlr9 (Tlr9-/-) with DEN/CCl4 for 24 weeks. As a second model, we used hepatocyte-specific Nemo knockout (NemoΔhepa) mice and generated double knockout (NemoΔhepaTlr9-/-) animals. RESULTS We show that Tlr9 is in the liver primarily expressed in Kupffer cells, suggesting a key role of Tlr9 in intercellular communication during hepatic injury. Tlr9 deletion resulted in reduced liver fibrosis as well as tumor burden. We observed down-regulation of hepatic stellate cell activation and consequently decreased collagen production in both models. Tlr9 deletion was associated with decreased apoptosis and compensatory proliferation of hepatocytes, modulating the initiation and progression of hepatocarcinogenesis. These findings were accompanied by a decrease in interferon-β and an increase in chemokines having an anti-tumoral effect. CONCLUSIONS Our data define Tlr9 as an important receptor involved in fibrogenesis, but also in the initiation and progression of hepatocellular carcinoma during chronic liver diseases.
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Affiliation(s)
- Hannes Hatten
- University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
| | - Leticia Colyn
- University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany.
| | - Ines Volkert
- University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
| | - Nikolaus Gaßler
- Institute of Forensic Medicine, Section Pathology, University Hospital of Jena, Jena, Germany
| | - Twan Lammers
- University Hospital RWTH Aachen, Institute for Experimental Molecular Imaging (ExMI), Aachen, Germany
| | - Ute Hofmann
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany
| | - Kai Markus Schneider
- University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany
| | - Christian Trautwein
- University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany; Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.
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4
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Vesković M, Pejović M, Šutulović N, Hrnčić D, Rašić-Marković A, Stanojlović O, Mladenović D. Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison. Int J Mol Sci 2024; 25:7405. [PMID: 39000518 PMCID: PMC11242866 DOI: 10.3390/ijms25137405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.
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Affiliation(s)
- Milena Vesković
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotića 9, 11000 Belgrade, Serbia
| | - Milka Pejović
- Primary Health Center “Vračar”, Velimira Bate Živojinovića 16, 11000 Belgrade, Serbia
| | - Nikola Šutulović
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Dragan Hrnčić
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Aleksandra Rašić-Marković
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Olivera Stanojlović
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Dušan Mladenović
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotića 9, 11000 Belgrade, Serbia
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Kodama T, Takehara T. Molecular Genealogy of Metabolic-associated Hepatocellular Carcinoma. Semin Liver Dis 2024; 44:147-158. [PMID: 38499207 PMCID: PMC11245329 DOI: 10.1055/a-2289-2298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC.
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Affiliation(s)
- Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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7
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Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab 2024; 15:20420188241242937. [PMID: 38628492 PMCID: PMC11020731 DOI: 10.1177/20420188241242937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/22/2024] [Indexed: 04/19/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is becoming a significant contributor to chronic liver disease globally, surpassing other etiologies, such as viral hepatitis. Prevention and early treatment strategies to curb its growing prevalence are urgently required. Recent evidence suggests that targeting the gut microbiota may help treat and alleviate disease progression in patients with MAFLD. This review aims to explore the complex relationship between MAFLD and the gut microbiota in relation to disease pathogenesis. Additionally, it delves into the therapeutic strategies targeting the gut microbiota, such as diet, exercise, antibiotics, probiotics, synbiotics, glucagon-like peptide-1 receptor agonists, and fecal microbiota transplantation, and discusses novel biomarkers, such as microbiota-derived testing and liquid biopsy, for their diagnostic and staging potential. Overall, the review emphasizes the urgent need for preventive and therapeutic strategies to address the devastating consequences of MAFLD at both individual and societal levels and recognizes that further exploration of the gut microbiota may open avenues for managing MAFLD effectively in the future.
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Affiliation(s)
- Waleed Alghamdi
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Division of Gastroenterology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saleh A. Alqahtani
- Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Baltimore, MD, USA
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8
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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9
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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10
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [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] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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11
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Huang C, Mei S, Zhang X, Tian X. Inflammatory Milieu Related to Dysbiotic Gut Microbiota Promotes Tumorigenesis of Hepatocellular Carcinoma. J Clin Gastroenterol 2023; 57:782-788. [PMID: 37406184 DOI: 10.1097/mcg.0000000000001883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an invasive primary liver cancer caused by multiple pathogenic factors and is a significant global health concern. With few effective therapeutic options, HCC is a heterogeneous carcinoma that typically arises in an inflammatory environment. Recent studies have suggested that dysbiotic gut microbiota is involved in hepatocarcinogenesis via multiple mechanisms. In this review, we discuss the effects of gut microbiota, microbial components, and microbiota-derived metabolites on the promotion and progression of HCC by feeding a persistent inflammatory milieu. In addition, we discuss the potential therapeutic modalities for HCC targeting the inflammatory status induced by gut microbiota. A better understanding of the correlation between the inflammatory milieu and gut microbiota in HCC may be beneficial for developing new therapeutic strategies and managing the disease.
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Affiliation(s)
- Caizhi Huang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Department of Laboratory Medicine, Hunan Children's Hospital
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine
| | - Xue Zhang
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
| | - Xuefei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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12
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Bragazzi MC, Venere R, Vignone A, Alvaro D, Cardinale V. Role of the Gut–Liver Axis in the Pathobiology of Cholangiopathies: Basic and Clinical Evidence. Int J Mol Sci 2023; 24:ijms24076660. [PMID: 37047635 PMCID: PMC10095354 DOI: 10.3390/ijms24076660] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
The “Gut–Liver Axis” refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut–liver axis in the pathogenesis of cholangiopathies.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, 04100 Roma, Italy
| | - Rosanna Venere
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, 04100 Roma, Italy
| | - Anthony Vignone
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
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13
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Bai YM, Liang S, Zhou B. Revealing immune infiltrate characteristics and potential immune-related genes in hepatic fibrosis: based on bioinformatics, transcriptomics and q-PCR experiments. Front Immunol 2023; 14:1133543. [PMID: 37122694 PMCID: PMC10140356 DOI: 10.3389/fimmu.2023.1133543] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/28/2023] [Indexed: 05/02/2023] Open
Abstract
Background The occurrence and progression of hepatic fibrosis (HF) is accompanied by inflammatory damage. Immune genes play a pivotal role in fibrogenesis and inflammatory damage in HF by regulating immune cell infiltration. However, the immune mechanisms of HF are inadequately studied. Therefore, this research aims to identify the immune genes and biological pathway which involved in fibrosis formation and inflammatory damage in HF and explore immune target-based therapeutics for HF. Methods The expression dataset GSE84044 of HF was downloaded from the GEO database. The crucial module genes for HF were screened according to weighted gene co-expression network analysis (WGCNA). The crucial module genes were mapped to immune-related genes obtained from the ImmPort database to obtain the hepatic fibrosis immune genes (HFIGs). In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on HFIGs. Then, the protein-protein interaction (PPI) network was conducted on HFIGs and hub genes were identified from the PPI network. Moreover, immune infiltration analysis was performed to identified correlation between hub gene and immune cell infiltration. To verify the reliability of the GSE84044 expression profile data analysis, a rat model of CCl4-induced HF was established, followed by transcriptome sequencing and immunofluorescence analysis and quantitative reverse transcription (q-PCR) experiments were performed in HF rats and normal rat liver tissues. Finally, CMAP platform was used to explore immune target-based therapeutics for HF. Results In the bioinformatics analysis of GSE84044 data, 98 HFIGs were screened. These genes were mainly involved in inflammation-related biological pathways such as NOD-like receptor signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway and PI3K-Akt signaling pathway. From the PPI network, 10 hub genes were identified, including CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2. Immune infiltration analysis showed that immune cells like neutrophils, natural killer (NK) cells, macrophages M1 and macrophages M2 were significantly correlated with the hepatic fibrosis process and hub gene expression was significantly correlated with these immune cells. Notably, most of the biological pathways HFIGs riched and all the hub gene expression except CXCL8 were validated in subsequent transcriptome and qRCR experiments. Finally, 15 small molecule compounds with the potential to reverse the high expression of hub genes were screen out as potential therapeutic agents for HF. Conclusion The immune genes CXCL8, IL18, CXCL10, CD8A, IL7, PTPRC, CCL5, IL7R, CXCL9 and CCL2 may play an essential role in the fibrosis formation and inflammatory damage in HF. The outcomes of this research provide a basis for the study of the immune mechanisms of HF and contribute to the diagnosis and prevention and treatment of HF in clinical practice.
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Affiliation(s)
- Yan-Ming Bai
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
| | - Shuang Liang
- Yinchuan Hospital of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
| | - Bo Zhou
- School of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China
- Ningxia Regional Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of High Incidence, Ningxia Medical University, Yinchuan, China
- *Correspondence: Bo Zhou,
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Khanmohammadi S, Kuchay MS. Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease. Pharmacol Res 2022; 185:106507. [DOI: 10.1016/j.phrs.2022.106507] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 10/31/2022]
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Liakina V, Strainiene S, Stundiene I, Maksimaityte V, Kazenaite E. Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis. World J Hepatol 2022; 14:1277-1290. [PMID: 36158907 PMCID: PMC9376773 DOI: 10.4254/wjh.v14.i7.1277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/27/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.
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Affiliation(s)
- Valentina Liakina
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Gediminas Technical University (VILNIUS TECH), Vilnius 10223, Lithuania.
| | - Sandra Strainiene
- Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Therapeutic and Radiological Department, Antakalnis Polyclinic, Vilnius 10207, Lithuania
| | - Ieva Stundiene
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
| | - Vaidota Maksimaityte
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
| | - Edita Kazenaite
- Centre of Hepatology, Gastroenterology and Dietetics, Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
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New-Aaron M, Dagur RS, Koganti SS, Ganesan M, Wang W, Makarov E, Ogunnaike M, Kharbanda KK, Poluektova LY, Osna NA. Alcohol and HIV-Derived Hepatocyte Apoptotic Bodies Induce Hepatic Stellate Cell Activation. BIOLOGY 2022; 11:1059. [PMID: 36101437 PMCID: PMC9312505 DOI: 10.3390/biology11071059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022]
Abstract
Recently, we found that both HIV and acetaldehyde, an alcohol metabolite, induce hepatocyte apoptosis, resulting in the release of large extracellular vesicles called apoptotic bodies (ABs). The engulfment of these hepatocyte ABs by hepatic stellate cells (HSC) leads to their profibrotic activation. This study aims to establish the mechanisms of HSC activation after engulfment of ABs from acetaldehyde and HIV-exposed hepatocytes (ABAGS+HIV). In vitro experiments were performed on Huh7.5-CYP (RLW) cells to generate hepatocyte ABs and LX2 cells were used as HSC. To generate ABs, RLW cells were pretreated for 24 h with acetaldehyde, then exposed overnight to HIV1ADA and to acetaldehyde for 96 h. Thereafter, ABs were isolated from cell suspension by a differential centrifugation method and incubated with LX2 cells (3:1 ratio) for profibrotic genes and protein analyses. We found that HSC internalized ABs via the tyrosine kinase receptor, Axl. While the HIV gag RNA/HIV proteins accumulated in ABs elicited no productive infection in LX2 and immune cells, they triggered ROS and IL6 generation, which, in turn, activated profibrotic genes via the JNK-ERK1/2 and JAK-STAT3 pathways. Similarly, ongoing profibrotic activation was observed in immunodeficient NSG mice fed ethanol and injected with HIV-derived RLW ABs. We conclude that HSC activation by hepatocyte ABAGS+HIV engulfment is mediated by ROS-dependent JNK-ERK1/2 and IL6 triggering of JAK-STAT3 pathways. This can partially explain the mechanisms of liver fibrosis development frequently observed among alcohol abusing PLWH.
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Affiliation(s)
- Moses New-Aaron
- Department of Environmental Health, Occupational Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
| | - Raghubendra Singh Dagur
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
| | - Siva Sankar Koganti
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Weimin Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA; (W.W.); (E.M.); (L.Y.P.)
| | - Edward Makarov
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA; (W.W.); (E.M.); (L.Y.P.)
| | - Mojisola Ogunnaike
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA; (W.W.); (E.M.); (L.Y.P.)
| | - Natalia A. Osna
- Department of Environmental Health, Occupational Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (R.S.D.); (S.S.K.); (M.G.); (M.O.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA; (W.W.); (E.M.); (L.Y.P.)
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Wang L, Cao ZM, Zhang LL, Li JM, Lv WL. The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective. Front Immunol 2022; 13:923599. [PMID: 35911738 PMCID: PMC9326173 DOI: 10.3389/fimmu.2022.923599] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota is a microecosystem composed of various microorganisms. It plays an important role in human metabolism, and its metabolites affect different tissues and organs. Intestinal flora maintains the intestinal mucosal barrier and interacts with the immune system. The liver is closely linked to the intestine by the gut-liver axis. As the first organ that comes into contact with blood from the intestine, the liver will be deeply influenced by the gut microbiota and its metabolites, and the intestinal leakage and the imbalance of the flora are the trigger of the pathological reaction of the liver. In this paper, we discuss the role of gut microbiota and its metabolites in the pathogenesis and development of autoimmune liver diseases((including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), metabolic liver disease such as non-alcoholic fatty liver disease, cirrhosisits and its complications, and liver cancer from the perspective of immune mechanism. And the recent progress in the treatment of these diseases was reviewed from the perspective of gut microbiota.
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Affiliation(s)
- Li Wang
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | - Zheng-Min Cao
- *Correspondence: Li Wang, ; Zheng-Min Cao, ; Juan-mei Li, ; Wen-liang Lv,
| | | | - Juan-mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen-liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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18
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MyD88 in hepatic stellate cells enhances liver fibrosis via promoting macrophage M1 polarization. Cell Death Dis 2022; 13:411. [PMID: 35484116 PMCID: PMC9051099 DOI: 10.1038/s41419-022-04802-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/19/2022] [Accepted: 03/30/2022] [Indexed: 11/08/2022]
Abstract
During liver fibrosis, quiescent HSCs (qHSCs) are activated to become activated HSCs (aHSCs)/myofibroblasts. The signal adapter MyD88, an essential component of TLR signaling, plays an important role in liver fibrosis. However, far less is known about the specific effects of MyD88 signaling in both qHSCs and aHSCs in the progress of liver fibrosis. Here, we used a CCl4-induced mouse fibrosis model in which MyD88 was selectively depleted in qHSCs (GFAPMyD88−/− mice) or aHSCs (α-SMAMyD88−/− mice). MyD88 deficiency in qHSCs or aHSCs attenuated liver fibrosis in mice and inhibited α-SMA-positive cell activation. Inhibition of MyD88 in HSCs decreased α-SMA and collagen I levels, inflammatory cell infiltration, and pro-inflammatory gene expression. Furthermore, MyD88 signaling in HSCs increased the secretion of CXCL10, which promoted macrophage M1 polarization through CXCR3, leading to activation of the JAK/STAT1 pathway. Inhibition of CXCL10 attenuated macrophage M1 polarization and reduced liver fibrosis. Thus, MyD88 signaling in HSCs crucially contributes to liver fibrosis and provides a promising therapeutic target for the prevention and treatment of liver fibrosis.
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. Possible relationship between IL28B rs12979860 and TLR2 -196 to -174 del/ins polymorphisms and the liver fibrosis stage in hepatitis C patients. Arch Virol 2022; 167:153-161. [PMID: 34817649 DOI: 10.1007/s00705-021-05302-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 10/01/2021] [Indexed: 10/19/2022]
Abstract
It has been shown that host factors play an important role in the progression of hepatitis C virus (HCV) infection. Toll-like receptor 2 (TLR2) del and interleukin 28B (IL28B) T alleles can mediate liver inflammation and pathogenesis of hepatocellular carcinoma. In the present study, the possible relationship between the IL28B rs12979860 C/T and TLR2 -196 to -174 del/ins gene variants and different fibrosis stages and host factors in hepatitis C patients was investigated. IL28B and TLR2 polymorphisms in the blood of 50 hepatitis C patients at different stages of fibrosis (24 mild/moderate, 26 advanced) and 24 healthy controls were examined by RT-qPCR. The highest frequency of the TLR2 del (26.9%) and IL28B T (46.2%) alleles was found in hepatitis C patients with the most advanced fibrosis, and the lowest frequency was found in healthy controls. There was a statistically significant difference between hepatitis C patients with advanced fibrosis and healthy controls in terms of the TLR2 del (p = 0.0062) and IL28B T (p = 0.0017) allele frequencies. However, no statistically significant difference was found between the mild/moderate fibrosis and severe fibrosis patient groups in terms of genotype or IL28B and TLR2 polymorphisms (p > 0.05). In addition, there was a significant difference between patients with mild/moderate or advanced fibrosis who carried the TLR2 del allele together with the IL28B CT genotype and healthy controls. The present study emphasizes that the TLR2 and IL28B gene variants cannot be single biomarkers for the determination of fibrosis stage in hepatitis C infection but together can play an important role in predicting severe disease.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Mersin University Faculty of Pharmacy, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Mersin University Faculty of Medicine, Mersin, Turkey
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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Gao Y, Nepal N, Jin SZ. Toll-like receptors and hepatitis C virus infection. Hepatobiliary Pancreat Dis Int 2021; 20:521-529. [PMID: 34419367 DOI: 10.1016/j.hbpd.2021.07.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 07/26/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a worldwide issue. However, the current treatment for hepatitis C has many shortcomings. Toll-like receptors (TLRs) are pattern recognition receptors involved in HCV infection, and an increasing number of studies are focusing on the role of TLRs in the progression of hepatitis C. DATA SOURCES We performed a PubMed search up to January 2021 with the following keywords: hepatitis C, toll-like receptors, interferons, inflammation, and immune evasion. We also used terms such as single-nucleotide polymorphisms (SNPs), susceptibility, fibrosis, cirrhosis, direct-acting antiviral agents, agonists, and antagonists to supplement the query results. We reviewed relevant publications analyzing the correlation between hepatitis C and TLRs and the role of TLRs in HCV infection. RESULTS TLRs 1-4 and 6-9 are involved in the process of HCV infection. When the host is exposed to the HCV, TLRs, as important participants in HCV immune evasion, trigger innate immunity to remove the virus and also promote inflammation and liver fibrosis. TLR gene SNPs affect hepatitis C susceptibility, treatment, and prognosis. The contribution of each TLR to HCV is different. Drugs targeting various TLRs are developed and validated, and TLRs can synergize with classic hepatitis C drugs, including interferon and direct-acting antiviral agents, constituting a new direction for the treatment of hepatitis C. CONCLUSIONS TLRs are important receptors in HCV infection. Different TLRs induce different mechanisms of virus clearance and inflammatory response. Although TLR-related antiviral therapy strategies exist, more studies are needed to explore the clinical application of TLR-related drugs.
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Affiliation(s)
- Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Narayan Nepal
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Shi-Zhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
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22
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Getachew A, Hussain M, Huang X, Li Y. Toll-like receptor 2 signaling in liver pathophysiology. Life Sci 2021; 284:119941. [PMID: 34508761 DOI: 10.1016/j.lfs.2021.119941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/19/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022]
Abstract
Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China.
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23
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Farooq M, Batool M, Kim MS, Choi S. Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies. Front Cell Dev Biol 2021; 9:756315. [PMID: 34671606 PMCID: PMC8522911 DOI: 10.3389/fcell.2021.756315] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.
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Affiliation(s)
- Mariya Farooq
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Maria Batool
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Suwon, South Korea
| | - Moon Suk Kim
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Suwon, South Korea
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24
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Abstract
Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis.
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25
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Giraud J, Saleh M. Host-Microbiota Interactions in Liver Inflammation and Cancer. Cancers (Basel) 2021; 13:cancers13174342. [PMID: 34503151 PMCID: PMC8430654 DOI: 10.3390/cancers13174342] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is a difficult to treat liver cancer that generally arises in individuals suffering from alcoholic or non-alcoholic fatty liver diseases. Inflammation, tissue injury and fibrosis are important precursors of HCC. In this review, we explore the links between the microbiota, inflammation and carcinogenesis in the context of HCC. We discuss how the gut and liver communicate and how microbial molecules, including structural components and metabolites, elicit inflammation and tumorigenesis in the liver. A better understanding of microbiota-dependent mechanisms of liver cancer development might lead to novel microbial-based therapeutic approaches. Abstract Hepatocellular carcinoma (HCC) is a classical inflammation-promoted cancer that occurs in a setting of liver diseases, including nonalcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD). These pathologies share key characteristics, notably intestinal dysbiosis, increased intestinal permeability and an imbalance in bile acids, choline, fatty acids and ethanol metabolites. Translocation of microbial- and danger-associated molecular patterns (MAMPs and DAMPs) from the gut to the liver elicits profound chronic inflammation, leading to severe hepatic injury and eventually HCC progression. In this review, we first describe how the gut and the liver communicate and discuss mechanisms by which the intestinal microbiota elicit hepatic inflammation and HCC. We focus on the role of microbial products, e.g., MAMPs, host inflammatory effectors and host–microbiome-derived metabolites in tumor-promoting mechanisms, including cell death and senescence. Last, we explore the potential of harnessing the microbiota to treat liver diseases and HCC.
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Affiliation(s)
- Julie Giraud
- ImmunoConcEpT, CNRS, UMR 5164, University of Bordeaux, F-33000 Bordeaux, France;
| | - Maya Saleh
- ImmunoConcEpT, CNRS, UMR 5164, University of Bordeaux, F-33000 Bordeaux, France;
- Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada
- Correspondence:
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26
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Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review. Int J Mol Sci 2021; 22:ijms22115801. [PMID: 34071550 PMCID: PMC8198390 DOI: 10.3390/ijms22115801] [Citation(s) in RCA: 276] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/15/2021] [Accepted: 05/24/2021] [Indexed: 12/24/2022] Open
Abstract
Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.
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27
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Qin T, Fu J, Verkade HJ. The role of the gut microbiome in graft fibrosis after pediatric liver transplantation. Hum Genet 2021; 140:709-724. [PMID: 32920649 PMCID: PMC8052232 DOI: 10.1007/s00439-020-02221-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/29/2020] [Indexed: 12/18/2022]
Abstract
Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the post-LT fibrogenesis, however, to date, neither of the factors seems to fully explain the cause of graft fibrosis. Recently, evidence has accumulated on the important role of the gut microbiome in outcomes after solid organ transplantation. As an altered microbiome is present in pediatric patients with end-stage liver diseases, we hypothesize that the persisting alterations in microbial composition or function contribute to the development of graft fibrosis, for example by bacteria translocation due to increased intestinal permeability, imbalanced bile acids metabolism, and/or decreased production of short-chain fatty acids (SCFAs). Subsequently, an immune response can be activated in the graft, together with the stimulation of fibrogenesis. Here we review current knowledge about the potential mechanisms by which alterations in microbial composition or function may lead to graft fibrosis in pediatric LT and we provide prospective views on the efficacy of gut microbiome manipulation as a therapeutic target to alleviate the graft fibrosis and to improve long-term survival after LT.
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Affiliation(s)
- Tian Qin
- Pediatric Gastroenterology/Hepatology, Section of Nutrition and Metabolism, Research Laboratory of Pediatrics, Department of Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
| | - Jingyuan Fu
- Pediatric Gastroenterology/Hepatology, Section of Nutrition and Metabolism, Research Laboratory of Pediatrics, Department of Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Henkjan J Verkade
- Pediatric Gastroenterology/Hepatology, Section of Nutrition and Metabolism, Research Laboratory of Pediatrics, Department of Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
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28
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Hrncir T, Hrncirova L, Kverka M, Hromadka R, Machova V, Trckova E, Kostovcikova K, Kralickova P, Krejsek J, Tlaskalova-Hogenova H. Gut Microbiota and NAFLD: Pathogenetic Mechanisms, Microbiota Signatures, and Therapeutic Interventions. Microorganisms 2021; 9:microorganisms9050957. [PMID: 33946843 PMCID: PMC8146698 DOI: 10.3390/microorganisms9050957] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Its worldwide prevalence is rapidly increasing and is currently estimated at 24%. NAFLD is highly associated with many features of the metabolic syndrome, including obesity, insulin resistance, hyperlipidaemia, and hypertension. The pathogenesis of NAFLD is complex and not fully understood, but there is increasing evidence that the gut microbiota is strongly implicated in the development of NAFLD. In this review, we discuss the major factors that induce dysbiosis of the gut microbiota and disrupt intestinal permeability, as well as possible mechanisms leading to the development of NAFLD. We also discuss the most consistent NAFLD-associated gut microbiota signatures and immunological mechanisms involved in maintaining the gut barrier and liver tolerance to gut-derived factors. Gut-derived factors, including microbial, dietary, and host-derived factors involved in NAFLD pathogenesis, are discussed in detail. Finally, we review currently available diagnostic and prognostic methods, summarise latest knowledge on promising microbiota-based biomarkers, and discuss therapeutic strategies to manipulate the microbiota, including faecal microbiota transplantation, probiotics and prebiotics, deletions of individual strains with bacteriophages, and blocking the production of harmful metabolites.
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Affiliation(s)
- Tomas Hrncir
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
- Correspondence:
| | - Lucia Hrncirova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Miloslav Kverka
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Robert Hromadka
- NEXARS (C2P), The Campus Science Park, 625 00 Brno, Czech Republic;
| | - Vladimira Machova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Eva Trckova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Klara Kostovcikova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Pavlina Kralickova
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Jan Krejsek
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Helena Tlaskalova-Hogenova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
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29
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Abstract
Clinical disorders that impair bile flow result in retention of bile acids and cholestatic liver injury, characterized by parenchymal cell death, bile duct proliferation, liver inflammation and fibrosis. However, the pathogenic role of bile acids in the development of cholestatic liver injury remains incompletely understood. In this review, we summarize the current understanding of this process focusing on the experimental and clinical evidence for direct effects of bile acids on each major cellular component of the liver: hepatocytes, cholangiocytes, stellate cells and immune cells. During cholestasis bile acids accumulated in the liver, causing oxidative stress and mitochondrial injury in hepatocytes. The stressed hepatocytes respond by releasing inflammatory cytokines through activation of specific signaling pathways and transcription factors. The recruited neutrophils and other immune cells then cause parenchymal cell death. In addition, bile acids also stimulate the proliferation of cholangiocytes and stellate cells that are responsible for bile duct proliferation and liver fibrosis. This review explores the evidence for bile acid involvement in these phenomena. The role of bile acid receptors, TGR5, FXR and the sphingosine-1-phosphate receptor 2 and the inflammasome are also examined. We hope that better understanding of these pathologic effects will facilitate new strategies for treating cholestatic liver injury.
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Affiliation(s)
- Shi-Ying Cai
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
| | - James L Boyer
- Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA
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30
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Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients 2021; 13:nu13031018. [PMID: 33801133 PMCID: PMC8004151 DOI: 10.3390/nu13031018] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.
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Affiliation(s)
- Andreas Blesl
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Correspondence:
| | - Vanessa Stadlbauer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
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31
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Kwong EK, Puri P. Gut microbiome changes in Nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2021; 6:3. [PMID: 33409398 DOI: 10.21037/tgh.2020.02.18] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/11/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are some of the most common liver diseases worldwide. The human gut microbiome is dynamic and shifts in bacterial composition have been implicated in many diseases. Studies have shown that there is a shift in bacterial overgrowth favoring pro-inflammatory mediators in patients with advanced disease progression such as cirrhosis. Further investigation demonstrated that the transplantation of gut microbiota from advanced liver disease patients can reproduce severe liver inflammation and injury in mice. Various techniques in manipulating the gut microbiota have been attempted including fecal transplantation and probiotics. This review focuses on the changes in the gut microbiota as well as emerging lines of microbiome work with respect to NAFLD and ALD.
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Affiliation(s)
- Eric K Kwong
- Department of Microbiology and Immunology, McGuire VA Medical Center, Richmond, VA, USA
| | - Puneet Puri
- Section of Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center, Richmond, VA, USA.,Virginia Commonwealth University, Richmond, VA, USA
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32
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The Gut Microbiota: How Does It Influence the Development and Progression of Liver Diseases. Biomedicines 2020; 8:biomedicines8110501. [PMID: 33207562 PMCID: PMC7697996 DOI: 10.3390/biomedicines8110501] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
The gut–liver axis plays important roles in both the maintenance of a healthy liver and the pathogenesis of liver diseases, where the gut microbiota acts as a major determinant of this relationship. Gut bacteria-derived metabolites and cellular components are key molecules that affect the function of the liver and modulate the pathology of liver diseases. Accumulating evidence showed that gut microbiota produces a myriad of molecules, including lipopolysaccharide, lipoteichoic acid, peptidoglycan, and DNA, as well as short-chain fatty acids, bile acids, trimethylamine, and indole derivatives. The translocation of these components to the liver exerts beneficial or pathogenic effects by interacting with liver immune cells. This is a bidirectional relationship. Therefore, the existence of crosstalk between the gut and liver and its implications on host health and diseases are essential for the etiology and treatment of diseases. Several mechanisms have been proposed for the pathogenesis of liver diseases, but still, the mechanisms behind the pathogenic role of gut-derived components on liver pathogenesis remain elusive and not understandable. This review discusses the current progress on the gut microbiota and its components in terms of the progression of liver diseases, and in turn, how liver diseases indirectly affect the intestinal function and induce intestinal inflammation. Moreover, this paper highlights the current therapeutic and preventive strategies used to restore the gut microbiota composition and improve host health.
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Żeromski J, Kierepa A, Brzezicha B, Kowala-Piaskowska A, Mozer-Lisewska I. Pattern Recognition Receptors: Significance of Expression in the Liver. Arch Immunol Ther Exp (Warsz) 2020; 68:29. [PMID: 32944845 PMCID: PMC7498499 DOI: 10.1007/s00005-020-00595-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Pattern recognition receptors (PRRs) are a pivotal part of the immune system. They are distributed in almost every site of higher organisms, able to recognize foreign pathogens or unwanted remnants of metabolism and mount innate immune response. Moreover, PRRs create bridging signaling to initiate adaptive immunity. The liver being the largest organ of the body, exposed to myriads of foreign substances often being immunogenic, is well equipped with PRRs. They act as sentinels of the organ, both in health and disease. In viral hepatitis C at least two of them, RIG-1 and TLR3 sense HCV, induce protective interferon production and create proinflammatory status. The hepatitis B virus is apparently invisible to PRRs, which has recently been denied. Besides, they are active in the course of infection. In liver injury and hepatic fibrogenesis Toll-like receptors (TLRs), predominantly TLR4, TLR3 and TLR9 are associated with gut microflora-related products and DNA from dying hepatocytes, lead to the activation of hepatic stellate cells. The latter initiate production of fibrillar collagens, the main agents forming hepatic fibrosis. Tumor cells of primary liver cancer also express PRRs, mainly TLRs. In concert with non-resolving liver inflammation, they are considered pivotal factors leading to carcinogenesis.
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Affiliation(s)
- Jan Żeromski
- Chair of Pathomorphology and Clinical Immunology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
| | - Agata Kierepa
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Bartosz Brzezicha
- Chair of Pathomorphology and Clinical Immunology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Arleta Kowala-Piaskowska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Iwona Mozer-Lisewska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
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34
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Di Ciaula A, Baj J, Garruti G, Celano G, De Angelis M, Wang HH, Di Palo DM, Bonfrate L, Wang DQH, Portincasa P. Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk. J Clin Med 2020; 9:2648. [PMID: 32823983 PMCID: PMC7465294 DOI: 10.3390/jcm9082648] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/07/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Giuseppe Celano
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Domenica Maria Di Palo
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - David Q-H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
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Katsarou A, Moustakas II, Pyrina I, Lembessis P, Koutsilieris M, Chatzigeorgiou A. Metabolic inflammation as an instigator of fibrosis during non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:1993-2011. [PMID: 32536770 PMCID: PMC7267690 DOI: 10.3748/wjg.v26.i17.1993] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/09/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells (qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors (PRRs), expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes, Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.
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Affiliation(s)
- Angeliki Katsarou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- 251 Hellenic Airforce General Hospital, Athens 11525, Greece
| | - Ioannis I Moustakas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany
| | - Panagiotis Lembessis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany.
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Giuffrè M, Campigotto M, Campisciano G, Comar M, Crocè LS. A story of liver and gut microbes: how does the intestinal flora affect liver disease? A review of the literature. Am J Physiol Gastrointest Liver Physiol 2020; 318:G889-G906. [PMID: 32146836 DOI: 10.1152/ajpgi.00161.2019] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Each individual is endowed with a unique gut microbiota (GM) footprint that mediates numerous host-related physiological functions, such as nutrient metabolism, maintenance of the structural integrity of the gut mucosal barrier, immunomodulation, and protection against microbial pathogens. Because of increased scientific interest in the GM, its central role in the pathophysiology of many intestinal and extraintestinal conditions has been recognized. Given the close relationship between the gastrointestinal tract and the liver, many pathological processes have been investigated in the light of a microbial-centered hypothesis of hepatic damage. In this review we introduce to neophytes the vast world of gut microbes, including prevalent bacterial distribution in healthy individuals, how the microbiota is commonly analyzed, and the current knowledge of the role of GM in liver disease pathophysiology. Also, we highlight the potentials and downsides of GM-based therapy.
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Affiliation(s)
- Mauro Giuffrè
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy
| | - Michele Campigotto
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy
| | - Giuseppina Campisciano
- Istituto di Ricovero e Cura a Carattere Scientifico Materno Infantile Burlo Garofolo, Trieste, Italy
| | - Manola Comar
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy.,Istituto di Ricovero e Cura a Carattere Scientifico Materno Infantile Burlo Garofolo, Trieste, Italy
| | - Lory Saveria Crocè
- Dipartimento Universitario Clinico di Scienze Mediche Chirurgiche e della Salute, Università degli Studi di Trieste, Italy.,Clinica Patologie del Fegato, Azienda Sanitaria Universitaria Integrata di Trieste, Italy.,Fondazione Italiana Fegato, Trieste, Italy
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Zhou Z, Kim JW, Qi J, Eo SK, Lim CW, Kim B. Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β-Modulated IL-1 Receptor Antagonist in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:614-629. [PMID: 31972159 DOI: 10.1016/j.ajpath.2019.11.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/17/2019] [Accepted: 11/05/2019] [Indexed: 02/08/2023]
Abstract
Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)β markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNβ and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/β receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.
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Affiliation(s)
- Zixiong Zhou
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Jong-Won Kim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Jing Qi
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Seong Kug Eo
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Chae Woong Lim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea
| | - Bumseok Kim
- Biosafety Research Institute, and the BK21 Plus Program, College of Veterinary Medicine, Jeonbuk National University, Iksan, Jeonbuk, South Korea.
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Sommer J, Dorn C, Gäbele E, Bataille F, Freese K, Seitz T, Thasler WE, Büttner R, Weiskirchen R, Bosserhoff A, Hellerbrand C. Four-And-A-Half LIM-Domain Protein 2 (FHL2) Deficiency Aggravates Cholestatic Liver Injury. Cells 2020; 9:cells9010248. [PMID: 31963815 PMCID: PMC7016690 DOI: 10.3390/cells9010248] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Cholestasis occurs in different clinical circumstances and leads to severe hepatic disorders. The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein that modulates multiple signal transduction pathways in a tissue- and cell context-specific manner. In this study, we aimed to gain insight into the function of FHL2 in cholestatic liver injury. FHL2 expression was significantly increased in the bile duct ligation (BDL) model in mice. In Fhl2-deficient (Fhl2-ko) mice, BDL caused a more severe portal and parenchymal inflammation, extended portal fibrosis, higher serum transaminase levels, and higher pro-inflammatory and pro-fibrogenic gene expression compared to wild type (wt) mice. FHL2 depletion in HepG2 cells with siRNA resulted in a higher expression of the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) gene. Furthermore, FHL2-depleted HepG2 cells showed higher expression of markers for oxidative stress, lower B-cell lymphoma 2 (Bcl2) expression, and higher Bcl2-associated X protein (BAX) expression after stimulation with deoxycholic acid (DCA). In hepatic stellate cells (HSCs), FHL2 depletion caused an increased expression of TGF-β and several pro-fibrogenic matrix metalloproteinases. In summary, our study shows that deficiency in FHL2 aggravates cholestatic liver injury and suggests FHL2-mediated effects on bile acid metabolisms and HSCs as potential mechanisms for pronounced hepatocellular injury and fibrosis.
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Affiliation(s)
- Judith Sommer
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany; (J.S.); (K.F.); (T.S.); (A.B.)
| | - Christoph Dorn
- Institute of Pharmacy, University Regensburg, D-93053 Regensburg, Germany;
| | - Erwin Gäbele
- Department of Internal Medicine I, University Hospital Regensburg, D-93053 Regensburg, Germany;
| | - Frauke Bataille
- Institute of Pathology, University Regensburg, D-93049 Regensburg, Germany;
| | - Kim Freese
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany; (J.S.); (K.F.); (T.S.); (A.B.)
| | - Tatjana Seitz
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany; (J.S.); (K.F.); (T.S.); (A.B.)
| | | | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, D-50937 Cologne, Germany;
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074 Aachen, Germany;
| | - Anja Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany; (J.S.); (K.F.); (T.S.); (A.B.)
- Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstr. 17, D-91054 Erlangen, Germany; (J.S.); (K.F.); (T.S.); (A.B.)
- Comprehensive Cancer Center (CCC) Erlangen-EMN, D-91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-85-24644; Fax: +49-9131-85-22485
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Shepard CR. TLR9 in MAFLD and NASH: At the Intersection of Inflammation and Metabolism. Front Endocrinol (Lausanne) 2020; 11:613639. [PMID: 33584545 PMCID: PMC7880160 DOI: 10.3389/fendo.2020.613639] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/10/2020] [Indexed: 12/15/2022] Open
Abstract
Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease.
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Chen D, Le TH, Shahidipour H, Read SA, Ahlenstiel G. The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression. Cells 2019; 8:E1324. [PMID: 31717860 PMCID: PMC6912265 DOI: 10.3390/cells8111324] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 12/12/2022] Open
Abstract
Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis.
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Affiliation(s)
- Dishen Chen
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
| | - Thanh H. Le
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- School of Medicine, Western Sydney University, Campbelltown 2560, NSW, Australia
| | - Haleh Shahidipour
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
| | - Scott A. Read
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia; (D.C.); (T.H.L.); (H.S.)
- Blacktown Medical School, Western Sydney University, Blacktown 2148, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
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Kostallari E, Shah VH. Pericytes in the Liver. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:153-167. [PMID: 30937868 DOI: 10.1007/978-3-030-11093-2_9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver pericytes, commonly named hepatic stellate cells (HSCs), reside in the space between liver sinusoidal endothelial cells (LSECs) and hepatocytes. They display important roles in health and disease. HSCs ensure the storage of the majority of vitamin A in a healthy body, and they represent the major source of fibrotic tissue in liver disease. Surrounding cells, such as LSECs, hepatocytes, and Kupffer cells, present a significant role in modulating HSC behavior. Therapeutic strategies against liver disease are being currently developed, where HSCs represent an ideal target. In this chapter, we will discuss HSC quiescence and activation in the context of healthy liver and diseases, such as fibrosis, steatohepatitis, and hepatocellular carcinoma.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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42
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PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses. PLoS One 2019; 14:e0218003. [PMID: 31170232 PMCID: PMC6553779 DOI: 10.1371/journal.pone.0218003] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 05/22/2019] [Indexed: 01/09/2023] Open
Abstract
We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.
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Personnaz J, Piccolo E, Branchereau M, Filliol A, Paccoud R, Moreau E, Calise D, Riant E, Gourdy P, Heymes C, Schwabe RF, Dray C, Valet P, Pradère J. Macrophage-derived HMGB1 is dispensable for tissue fibrogenesis. FASEB Bioadv 2019; 1:227-245. [PMID: 32123829 PMCID: PMC6996376 DOI: 10.1096/fba.2018-00035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/11/2018] [Accepted: 12/14/2018] [Indexed: 12/19/2022] Open
Abstract
Alarmins and damage-associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell-specific deletion approaches, demonstrated that macrophage-derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1Flox mice, mice with macrophage-specific HMGB1 deletion (HMGB1ΔMac) do not display any modification of fibrogenesis in the liver after CCL4 or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1ΔMac mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage-derived HMGB1 does not contribute to tissue repair and fibrogenesis.
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Affiliation(s)
- Jean Personnaz
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Enzo Piccolo
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Maxime Branchereau
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | | | - Romain Paccoud
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Elsa Moreau
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Denis Calise
- UMS006, Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, Institute of Cardiovascular and Metabolic DiseaseToulouseFrance
| | - Elodie Riant
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Pierre Gourdy
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
- Service de Diabétologie, Maladies Métaboliques et Nutrition, CHU de ToulouseToulouseFrance
| | - Christophe Heymes
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | | | - Cédric Dray
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Philippe Valet
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
| | - Jean‐Philippe Pradère
- Institut des Maladies Métaboliques et Cardiovasculaires, UMR 1048/I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de ToulouseToulouseFrance
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Zhong Z, Lemasters JJ. A Unifying Hypothesis Linking Hepatic Adaptations for Ethanol Metabolism to the Proinflammatory and Profibrotic Events of Alcoholic Liver Disease. Alcohol Clin Exp Res 2018; 42:2072-2089. [PMID: 30132924 PMCID: PMC6214771 DOI: 10.1111/acer.13877] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/13/2018] [Indexed: 02/06/2023]
Abstract
The pathogenesis of alcoholic liver disease (ALD) remains poorly understood but is likely a multihit pathophysiological process. Here, we propose a hypothesis of how early mitochondrial adaptations for alcohol metabolism lead to ALD pathogenesis. Acutely, ethanol (EtOH) feeding causes a near doubling of hepatic EtOH metabolism and oxygen consumption within 2 to 3 hours. This swift increase in alcohol metabolism (SIAM) is an adaptive response to hasten metabolic elimination of both EtOH and its more toxic metabolite, acetaldehyde (AcAld). In association with SIAM, EtOH causes widespread hepatic mitochondrial depolarization (mtDepo), which stimulates oxygen consumption. In parallel, voltage-dependent anion channels (VDAC) in the mitochondrial outer membrane close. Together, VDAC closure and respiratory stimulation promote selective and more rapid oxidation of EtOH first to AcAld in the cytosol and then to nontoxic acetate in mitochondria, since membrane-permeant AcAld does not require VDAC to enter mitochondria. VDAC closure also inhibits mitochondrial fatty acid oxidation and ATP release, promoting steatosis and a decrease in cytosolic ATP. After acute EtOH, these changes revert as EtOH is eliminated with little hepatocellular cytolethality. mtDepo also stimulates mitochondrial autophagy (mitophagy). After chronic high EtOH exposure, the capacity to process depolarized mitochondria by mitophagy becomes compromised, leading to intra- and extracellular release of damaged mitochondria, mitophagosomes, and/or autolysosomes containing mitochondrial damage-associated molecular pattern (mtDAMP) molecules. mtDAMPs cause inflammasome activation and promote inflammatory and profibrogenic responses, causing hepatitis and fibrosis. We propose that persistence of mitochondrial responses to EtOH metabolism becomes a tipping point, which links initial adaptive EtOH metabolism to maladaptive changes initiating onset and progression of ALD.
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Affiliation(s)
- Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences and
| | - John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences and
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
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Roh YS, Kim JW, Park S, Shon C, Kim S, Eo SK, Kwon JK, Lim CW, Kim B. Toll-Like Receptor-7 Signaling Promotes Nonalcoholic Steatohepatitis by Inhibiting Regulatory T Cells in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2574-2588. [PMID: 30125542 DOI: 10.1016/j.ajpath.2018.07.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 06/09/2018] [Accepted: 07/10/2018] [Indexed: 12/17/2022]
Abstract
Toll-like receptor 7 (TLR7) signaling regulates the production of type 1 interferons (IFNs) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in nonalcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/β receptor 1-deficient, and Treg cell-depleted mice. TLR7-deficient and IFN-α/β receptor 1-deficient mice were more protective to steatohepatitis than WT mice. Of interest, both TNF-α and type 1 IFN promoted apoptosis of Treg cells involved in the prevention of NASH. Indeed, Treg cell-depleted mice had aggravated steatohepatitis compared with WT mice. Finally, treatment with immunoregulatory sequence 661, an antagonist of TLR7, efficiently ameliorated NASH in vivo. These results demonstrate that TLR7 signaling can induce TNF-α production in Kupffer cells and type I IFN production in dendritic cells. These cytokines subsequently induce hepatocyte death and inhibit Treg cells activities, leading to the progression of NASH. Thus, manipulating the TLR7-Treg cell axis might be used as a novel therapeutic strategy to treat NASH.
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46
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Antifibrotics in liver disease: are we getting closer to clinical use? Hepatol Int 2018; 13:25-39. [PMID: 30302735 DOI: 10.1007/s12072-018-9897-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 09/14/2018] [Indexed: 12/14/2022]
Abstract
The process of wound healing in response to chronic liver injury leads to the development of liver fibrosis. Regardless of etiology, the profound impact of the degree of liver fibrosis on the prognosis of chronic liver diseases has been well demonstrated. While disease-specific therapy, such as treatments for viral hepatitis, has been shown to reverse liver fibrosis and cirrhosis in both clinical trials and real-life practice, subsets of patients do not demonstrate fibrosis regression. Moreover, where disease-specific therapies are not available, the need for antifibrotics exists. Increased understanding into the pathogenesis of liver fibrosis sets the stage to focus on antifibrotic therapies attempting to: (1) Minimize liver injury and inflammation; (2) Inhibit liver fibrogenesis by enhancing or inhibiting target receptor-ligand interactions or intracellular signaling pathways; and (3) Promote fibrosis resolution. While no antifibrotic therapies are currently available, a number are now being evaluated in clinical trials, and their use is becoming closer to reality for select subsets of patients.
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Lemasters JJ, Zhong Z. Mitophagy in hepatocytes: Types, initiators and role in adaptive ethanol metabolism☆. LIVER RESEARCH 2018; 2:125-132. [PMID: 31157120 PMCID: PMC6541449 DOI: 10.1016/j.livres.2018.09.005] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mitophagy (mitochondrial autophagy) in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged, effete and superfluous mitochondria. Mitophagy has distinct variants. In type 1 mitophagy, typical of nutrient deprivation, cup-shaped sequestration membranes (phagophores) grow, surround and sequester individual mitochondria into mitophagosomes, often in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes, followed by fusion with lysosomes. By contrast, mitochondrial depolarization stimulates type 2 mitophagy, which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3 (LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission. Oppositely to type 1 mitophagy, the inhibition of phosphoinositide-3-kinase (PI3K) does not block type 2 mitophagy. In type 3 mitophagy, or micromitophagy, mitochondria-derived vesicles (MDVs) enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen. In response to ethanol feeding, widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism. As a consequence, type 2 mitophagy develops in response to the mitochondrial depolarization. After chronic high ethanol feeding, processing of depolarized mitochondria by mitophagy becomes compromised, leading to release of mitochondrial damage-associated molecular patterns (mtDAMPs) that promote inflammatory and profibrogenic responses. We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease (ALD).
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Affiliation(s)
- John J. Lemasters
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhi Zhong
- Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA
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48
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Abstract
Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit.
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Affiliation(s)
- Mara H Sherman
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon 97201, USA;
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49
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Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15:397-411. [PMID: 29748586 PMCID: PMC6319369 DOI: 10.1038/s41575-018-0011-z] [Citation(s) in RCA: 952] [Impact Index Per Article: 136.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the past decade, an exciting realization has been that diverse liver diseases - ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma - fall along a spectrum. Work on the biology of the gut-liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut-liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These 'avatar mice' could be especially useful for guiding new microbiome-based or microbiome-informed therapies.
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Affiliation(s)
- Anupriya Tripathi
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, CA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA
| | - Justine Debelius
- Department of Pediatrics, University of California, San Diego, CA, USA
| | - David A Brenner
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA
| | - Michael Karin
- Department of Pediatrics, University of California, San Diego, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, CA, USA.
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA.
- Center for Microbiome Innovation, University of California, San Diego, CA, USA.
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50
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Long-term oral atazanavir attenuates myocardial infarction-induced cardiac fibrosis. Eur J Pharmacol 2018; 828:97-102. [DOI: 10.1016/j.ejphar.2018.03.041] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 11/22/2022]
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