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1
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Wu Q, Yang Y, Lin S, Geller DA, Yan Y. The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC. Front Immunol 2025; 16:1569915. [PMID: 40370443 PMCID: PMC12074932 DOI: 10.3389/fimmu.2025.1569915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.
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Affiliation(s)
- Qiulin Wu
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yan Yang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shixun Lin
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - David A. Geller
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Yihe Yan
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Feng X, Feng B, Zhou J, Yang J, Pan Q, Yu J, Shang D, Li L, Cao H. Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells. Hepatology 2025; 81:1211-1227. [PMID: 38546278 PMCID: PMC11902620 DOI: 10.1097/hep.0000000000000831] [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] [Received: 09/25/2023] [Accepted: 02/09/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND AND AIMS The immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them a promising therapeutic approach for liver fibrosis (LF). Here, we postulated that MSCs could potentially suppress the pro-fibrotic activity of intrahepatic B cells, thereby inhibiting LF progression. APPROACH AND RESULTS Administration of MSCs significantly ameliorated LF as indicated by reduced myofibroblast activation, collagen deposition, and inflammation. The treatment efficacy of MSCs can be attributed to decreased infiltration, activation, and pro-inflammatory cytokine production of intrahepatic B cells. Single-cell RNA sequencing revealed a distinct intrahepatic B cell atlas, and a subtype of naive B cells (B-II) was identified, which were markedly abundant in fibrotic liver, displaying mature features with elevated expression of several proliferative and inflammatory genes. Transcriptional profiling of total B cells revealed that intrahepatic B cells displayed activation, proliferation, and pro-inflammatory gene profile during LF. Fibrosis was attenuated in mice ablated with B cells (μMT) or in vivo treatment with anti-CD20. Moreover, fibrosis was recapitulated in μMT after adoptive transfer of B cells, which in turn could be rescued by MSC injection, validating the pathogenic function of B cells and the efficacy of MSCs on B cell-promoted LF progression. Mechanistically, MSCs could inhibit the proliferation and cytokine production of intrahepatic B cells through exosomes, regulating the Mitogen-activated protein kinase and Nuclear factor kappa B signaling pathways. CONCLUSIONS Intrahepatic B cells serve as a target of MSCs, play an important role in the process of MSC-induced amelioration of LF, and may provide new clues for revealing the novel mechanisms of MSC action.
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Affiliation(s)
- Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Bing Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Jiahang Zhou
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Jinfeng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Qiaoling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
| | - Dandan Shang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City, China
| | - Lanjuan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan City, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
- National Medical Center for Infectious Diseases, Hangzhou City, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou City, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province, Hangzhou City, China
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Kim NH, Kim MY, Yang YM, Jeong WI, Lee HW, Kim W, Kang SG, Han YH. Bacterial components-driven intrahepatic CXCR5 hi B cells are important population for MASH progression through inducing inflammation. FASEB J 2025; 39:e70322. [PMID: 39812617 DOI: 10.1096/fj.202401256r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 12/17/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe liver inflammation and fibrosis due to an imbalanced immune response caused by enhanced bacterial components. The progression of MASH is closely linked to increased permeability of intestinal mucosal barrier facilitating enter of bacterial components into hepatic portal venous system. B cells are important immune cells for adaptive responses and enhance hepatic inflammation through cytokine production and T cell activation. B cells are influenced by gut microbiota, but the specific B cell populations in MASH and their pathologic mechanism remain obscure. Here, we found that the numbers of B cells highly expressing CXCR5, the receptor of CXCL13 chemokine, were increased in the livers of MASH. CXCR5 high B cells are non-proliferating naive B cells with inflammatory features mainly residing in hepatic parenchyma to affect liver pathology. Importantly, we revealed that CXCR5 high B cells were induced by bacterial components stimulating TLRs. These bacterial stimulator-induced CXCR5hi B cells highly express TNFα, CD80, and MHC class II, leading to T cell activation. Consistently, we confirmed that intravenous injection of CXCR5 high B cells enhanced hepatic inflammation in MASH model. Ultimately, this study elucidates the role and mechanisms of CXCR5 high B cells in advancing MASH progression.
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Affiliation(s)
- Nam-Hee Kim
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Mi-Yeon Kim
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Yoon Mee Yang
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
- Multidimentional Genomics Research Center, Kangwon National University, Chuncheon, South Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Hye Won Lee
- Department of Internal Medicine Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Wooseob Kim
- Department of Microbiology, Korea University College of Medicine, Seoul, South Korea
| | - Seung Goo Kang
- Department of Molecular Bioscience/Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, South Korea
| | - Yong-Hyun Han
- Department of Pharmacy, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
- Multidimentional Genomics Research Center, Kangwon National University, Chuncheon, South Korea
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4
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Gilgenkrantz H, Sayegh RA, Lotersztajn S. Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy. Annu Rev Pharmacol Toxicol 2025; 65:281-299. [PMID: 39259981 DOI: 10.1146/annurev-pharmtox-020524-012013] [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] [Indexed: 09/13/2024]
Abstract
Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.
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Affiliation(s)
- Helene Gilgenkrantz
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
| | - Rola Al Sayegh
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
| | - Sophie Lotersztajn
- Université Paris Cité, INSERM, UMR-S1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France;
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Wei X, Weng Z, Xu X, Yao J. Exploration of a miRNA-mRNA network shared between acute pancreatitis and Epstein-Barr virus infection by integrated bioinformatics analysis. PLoS One 2024; 19:e0311130. [PMID: 39546499 PMCID: PMC11567522 DOI: 10.1371/journal.pone.0311130] [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: 07/24/2024] [Accepted: 09/10/2024] [Indexed: 11/17/2024] Open
Abstract
Acute pancreatitis (AP) stands out as a primary cause of hospitalization within gastrointestinal ailments, attributed to diverse factors, including Epstein-Barr virus (EBV) infection. Nevertheless, the common miRNAs and genes shared between AP and EBV infection remain unclear. In the present study, four datasets GSE194331, GSE42455, GSE45918 and GSE109220 were selected and downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed to screen for differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Target genes of overlapping DEMs were predicted, and intersections with overlapping DEGs were used to construct a miRNA-mRNA network. In addition, the enrichment analysis, drug prediction, diagnostic accuracy assessment, competitive endogenous RNA (ceRNA) network construction, transcription factor (TF)-miRNA-mRNA network construction, and immune cell infiltration analysis were also carried out. We found a total of 111 genes and 8 miRNAs shared between AP and EBV infection. A miRNA-mRNA network was constructed, which comprised 5 miRNAs and 10 genes exhibiting robust diagnostic performance. Histone deacetylase (HDAC) inhibitor was identified as a novel therapeutic intervention from drug prediction analysis. The results of immune cell infiltration analysis revealed that a consistent and significant difference could be found on activated B cell in AP and EBV-infected individuals in comparison to the controls. Taken together, our work, for the first time, revealed a miRNA-mRNA network shared between AP and EBV infection, thereby enriching a deeper comprehension of the intricate molecular mechanisms and potential therapeutic targets entwined in these two pathological conditions.
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Affiliation(s)
- Xing Wei
- Department of Infectious Disease, The Nantong First People’s Hospital and The Affiliated Hospital 2 of Nantong University, Nantong, China
| | - Zhen Weng
- MOE Engineering Center of Hematological Disease, Soochow University, Suzhou, China
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xia Xu
- Department of Gastroenterology, The Second People’s Hospital of Nantong and The Affiliated Rehabilitation Hospital of Nantong University, Nantong, China
| | - Jian Yao
- Department of Infectious Disease, The Nantong First People’s Hospital and The Affiliated Hospital 2 of Nantong University, Nantong, China
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Alisi A, McCaughan G, Grønbæk H. Role of gut microbiota and immune cells in metabolic-associated fatty liver disease: clinical impact. Hepatol Int 2024; 18:861-872. [PMID: 38995341 DOI: 10.1007/s12072-024-10674-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/18/2024] [Indexed: 07/13/2024]
Abstract
In 2020, a revised definition of fatty liver disease associated with metabolic dysfunction (MAFLD) was proposed to replace non-alcoholic fatty liver (NAFLD). Liver steatosis and at least one of the three metabolic risk factors, including type 2 diabetes, obesity, or signs of metabolic dysregulation, are used to diagnose MAFLD. MAFLD, similarly to NAFLD, is characterized by a spectrum of disease ranging from simple steatosis to advanced metabolic steatohepatitis with or without fibrosis, and may progress to cirrhosis and liver cancer, including increased risk of other critical extrahepatic diseases. Even though the pathophysiology of MAFLD and potential therapeutic targets have been explored in great detail, there is yet no Food and Drug Administration approved treatment. Recently, gut microbiome-derived products (e.g., endotoxins and metabolites) involved in intestinal barrier disruption, systemic inflammation, and modification of intrahepatic immunity have been associated with MAFLD development and progression. Therefore, different strategies could be adopted to modify the gut microbiome to improve outcomes in early and progressive MAFLD. Here, we provide an overview of mechanisms that may link the gut microbiome and immune response during the onset of liver steatosis and progression to steatohepatitis and fibrosis in patients with MAFLD. Finally, gut microbiota-based approaches are discussed as potential personalized treatments against MAFLD.
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Affiliation(s)
- Anna Alisi
- Research Unit of Genetics of Complex Phenotypes, Bambino Gesu' Children Hospital, IRCCS, Rome, Italy.
| | - Geoffrey McCaughan
- A.W Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Sydney, Australia
- Centenary Institute, University of Sydney, Sydney, Australia
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital and Clinical Institute, Aarhus University, Aarhus, Denmark
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7
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Li H, Xia N. The multifaceted roles of B lymphocytes in metabolic dysfunction-associated steatotic liver disease. Front Immunol 2024; 15:1447391. [PMID: 39372417 PMCID: PMC11449700 DOI: 10.3389/fimmu.2024.1447391] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 09/05/2024] [Indexed: 10/08/2024] Open
Abstract
Recent evidence suggests that adaptive immune cells are important contributors to metabolic dysfunction-associated steatotic liver disease (MASLD, formerly non-alcoholic fatty liver disease, NAFLD). In liver biopsies from MASLD patients, the accumulation of intrahepatic B cells is positively correlated with the MASLD activity score. Hepatic B-cell infiltration is observed in experimental models of metabolic dysfunction-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis, NASH). Intrahepatic B2 cells have been shown to contribute to MASLD/MASH by activating T cells, macrophages and hepatic stellate cells, and by producing pathogenic IgG antibodies. In mice fed a MASH diet, selective depletion of B2 cells reduces steatohepatitis and fibrosis. Intestinal B cells are metabolically activated in MASH and promote T-cell activation independently of TCR signaling. In addition, B cells have been shown to contribute to liver fibrosis by activating monocyte-derived macrophages through the secretion of IgA immunoglobulins. Furthermore, our recent study indicates that certain B cell subsets, very likely regulatory B cells, may play a protective role in MASLD. This review summarizes the molecular mechanisms of B cell functions and discusses future research directions on the different roles of B cells in MASLD and MASH.
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Affiliation(s)
- Huige Li
- Department of Pharmacology, University Medical Center, Johannes Gutenberg
University, Mainz, Germany
| | - Ning Xia
- Department of Pharmacology, University Medical Center, Johannes Gutenberg
University, Mainz, Germany
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8
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Li Y, Quan X, Tai Y, Wu YT, Wei B, Wu H. Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis. World J Hepatol 2024; 16:1156-1166. [PMID: 39221101 PMCID: PMC11362904 DOI: 10.4254/wjh.v16.i8.1156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/24/2024] [Accepted: 08/02/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention. However, it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis. AIM To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization (MR) study. METHODS Data on 731 immunocyte phenotypes were obtained from genome-wide association studies. Liver cirrhosis data were derived from the Finn Gen dataset, which included 214403 individuals of European ancestry. We used inverse variable weighting as the primary analysis method to assess the causal relationship. Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis [P < 0.05, odds ratio (OR) > 1] and that 9 immunocyte phenotypes were negatively correlated with liver cirrhosis (P < 0.05, OR < 1). Liver cirrhosis was positively linked to 9 immune cell phenotypes (P < 0.05, OR > 1) and negatively linked to 10 immune cell phenotypes (P < 0.05; OR < 1). None of these associations showed heterogeneity or horizontally pleiotropy (P > 0.05). CONCLUSION This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis. These findings offer new directions for the treatment of liver cirrhosis.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yang Tai
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Department of Clinical Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Bo Wei
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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9
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Sun D, Xie C, Zhao Y, Liao J, Li S, Zhang Y, Wang D, Hua K, Gu Y, Du J, Huang G, Huang J. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med 2024; 30:104. [PMID: 39030473 PMCID: PMC11265038 DOI: 10.1186/s10020-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 07/21/2024] Open
Abstract
Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.
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Affiliation(s)
- Dayan Sun
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Chuanping Xie
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yong Zhao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Junmin Liao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Shuangshuang Li
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yanan Zhang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Dingding Wang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Kaiyun Hua
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yichao Gu
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Jingbin Du
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Guoxian Huang
- Department of Pediatric Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China
| | - Jinshi Huang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China.
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10
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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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11
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Halimani N, Nesterchuk M, Tsitrina AA, Sabirov M, Andreichenko IN, Dashenkova NO, Petrova E, Kulikov AM, Zatsepin TS, Romanov RA, Mikaelyan AS, Kotelevtsev YV. Knockdown of Hyaluronan synthase 2 suppresses liver fibrosis in mice via induction of transcriptomic changes similar to 4MU treatment. Sci Rep 2024; 14:2797. [PMID: 38307876 PMCID: PMC10837461 DOI: 10.1038/s41598-024-53089-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/27/2024] [Indexed: 02/04/2024] Open
Abstract
Hepatic fibrosis remains a significant clinical challenge due to ineffective treatments. 4-methylumbelliferone (4MU), a hyaluronic acid (HA) synthesis inhibitor, has proven safe in phase one clinical trials. In this study, we aimed to ameliorate liver fibrosis by inhibiting HA synthesis. We compared two groups of mice with CCl4-induced fibrosis, treated with 4-methylumbelliferone (4MU) and hyaluronan synthase 2 (HAS2) targeting siRNA (siHAS2). The administration of 4MU and siHAS2 significantly reduced collagen and HA deposition, as well as biochemical markers of hepatic damage induced by repeated CCl4 injections. The transcriptomic analysis revealed converging pathways associated with downstream HA signalling. 4MU- and siHAS2-treated fibrotic livers shared 405 upregulated and 628 downregulated genes. These genes were associated with xenobiotic and cholesterol metabolism, mitosis, endoplasmic reticulum stress, RNA processing, and myeloid cell migration. The functional annotation of differentially expressed genes (DEGs) in siHAS2-treated mice revealed attenuation of extracellular matrix-associated pathways. In comparison, in the 4MU-treated group, DEGs were related to lipid and bile metabolism pathways and cell cycle. These findings confirm that HAS2 is an important pharmacological target for suppressing hepatic fibrosis using siRNA.
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Affiliation(s)
- Noreen Halimani
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation and Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 143025, Russia.
| | - Mikhail Nesterchuk
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation and Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 143025, Russia
| | - Alexandra A Tsitrina
- IKI-Ilse Katz Institute for Nanoscale Science & Technology, Nem Gurion University of the Negev, Beersheba, Israel
| | - Marat Sabirov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 26 Vavilov Street, Moscow, 119334, Russia
| | - Irina N Andreichenko
- AO Reproduction Head Centre of Agricultural Animals, Tsentralnaya Street, 3., Podolsk, Moscow Region, 142143, Russia
| | - Nataliya O Dashenkova
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 26 Vavilov Street, Moscow, 119334, Russia
| | - Elizaveta Petrova
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation and Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 143025, Russia
| | - Alexey M Kulikov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 26 Vavilov Street, Moscow, 119334, Russia
| | - Timofei S Zatsepin
- Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia
| | - Roman A Romanov
- Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Arsen S Mikaelyan
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 26 Vavilov Street, Moscow, 119334, Russia
| | - Yuri V Kotelevtsev
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation and Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 143025, Russia
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12
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Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95:101231. [PMID: 38056058 DOI: 10.1016/j.mam.2023.101231] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/13/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023]
Abstract
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
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Affiliation(s)
- Maurizio Parola
- Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Corso Raffaello 30, 10125, Torino, Italy.
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine - Royal Free Hospital, London, NW32PF, United Kingdom.
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Chen C, Cai H, Shen J, Zhang X, Peng W, Li C, Lv H, Wen T. Exploration of a hypoxia-immune-related microenvironment gene signature and prediction model for hepatitis C-induced early-stage fibrosis. J Transl Med 2024; 22:116. [PMID: 38287425 PMCID: PMC10826039 DOI: 10.1186/s12967-024-04912-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 01/19/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Liver fibrosis contributes to significant morbidity and mortality in Western nations, primarily attributed to chronic hepatitis C virus (HCV) infection. Hypoxia and immune status have been reported to be significantly correlated with the progression of liver fibrosis. The current research aimed to investigate the gene signature related to the hypoxia-immune-related microenvironment and identify potential targets for liver fibrosis. METHOD Sequencing data obtained from GEO were employed to assess the hypoxia and immune status of the discovery set utilizing UMAP and ESTIMATE methods. The prognostic genes were screened utilizing the LASSO model. The infiltration level of 22 types of immune cells was quantified utilizing CIBERSORT, and a prognosis-predictive model was established based on the selected genes. The model was also verified using qRT-PCR with surgical resection samples and liver failure samples RNA-sequencing data. RESULTS Elevated hypoxia and immune status were linked to an unfavorable prognosis in HCV-induced early-stage liver fibrosis. Increased plasma and resting NK cell infiltration were identified as a risk factor for liver fibrosis progression. Additionally, CYP1A2, CBS, GSTZ1, FOXA1, WDR72 and UHMK1 were determined as hypoxia-immune-related protective genes. The combined model effectively predicted patient prognosis. Furthermore, the preliminary validation of clinical samples supported most of the conclusions drawn from this study. CONCLUSION The prognosis-predictive model developed using six hypoxia-immune-related genes effectively predicts the prognosis and progression of liver fibrosis. The current study opens new avenues for the future prediction and treatment of liver fibrosis.
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Affiliation(s)
- Chuwen Chen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Haozheng Cai
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Junyi Shen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Xiaoyun Zhang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Wei Peng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Chuan Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Haopeng Lv
- Department of General Surgery, ChengDu Shi Xinjin Qu Renmin Yiyuan: People's Hospital of Xinjin District, Chengdu, China
| | - Tianfu Wen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China.
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Zhang L, Zhao C, Dai W, Tong H, Yang W, Huang Z, Tang C, Gao J. Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis. Cell Mol Life Sci 2023; 80:379. [PMID: 38010435 PMCID: PMC11072584 DOI: 10.1007/s00018-023-05032-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/05/2023] [Accepted: 11/01/2023] [Indexed: 11/29/2023]
Abstract
B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-β signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-β or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
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Affiliation(s)
- Linhao Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Chong Zhao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Wenting Dai
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China
| | - Huan Tong
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenjuan Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhiyin Huang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chengwei Tang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China.
| | - Jinhang Gao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China.
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15
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Zhu N, Song Y, Zhang C, Wang K, Han J. Association between the peripheral neutrophil-to-lymphocyte ratio and metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes. Front Med (Lausanne) 2023; 10:1294425. [PMID: 38020132 PMCID: PMC10657835 DOI: 10.3389/fmed.2023.1294425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 10/25/2023] [Indexed: 12/01/2023] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes frequently co-occur, imposing a tremendous medical burden. A convenient and effective MASLD indicator will be beneficial to the early diagnosis of disease. In the clinical laboratory, the neutrophil-to-lymphocyte ratio (NLR) is a readily accessible hematological marker. This study designed to determine the relation between the NLR and MASLD in type 2 diabetes patients. Methods Data from 1,151 type 2 diabetes inpatients without infections, malignancy or hematological diseases who were recruited from 2016 through 2022 were analyzed in the retrospective study. The patients were stratified into NLR tertiles (total population: high NLR level > 2.18; middle NLR level: 1.58-2.18; low NLR level < 1.58), with additional subgroup stratification by sex (men: high NLR level > 2.21; middle NLR level: 1.60-2.21; and low NLR level < 1.60; women: high NLR level > 2.12; middle NLR level: 1.53-2.12; and low NLR level < 1.53). After adjusting for confounders (age, sex, weight, Glu, ALT and TG) associated with MASLD, the odds ratio (OR) and the corresponding 95% confidence interval (CI) of the NLR were obtained by using a binary logistic regression analysis to verify the correlation between the NLR and MASLD. Results Compared to non-MASLD patients, MASLD patients had higher weight, blood glucose, insulin and C-peptide, worse liver function (higher ALT and GGT), lower HDL (all p < 0.05), and lower NLR (p < 0.001). The prevalence of MASLD was 43.75% (high NLR level), 55.21% (middle NLR level) and 52.22% (low NLR level) (p < 0.05). Compared to those of the high NLR level, the adjusted ORs and 95% CIs of the middle and low NLR levels were 1.624 (95% CI: 1.141-2.311) and 1.456 (95% CI: 1.025-2.068), for all subjects, while they were 1.640 (95% CI: 1.000-2.689) and 1.685 (95% CI: 1.026-2.766), for men. Conclusion A low NLR is associated with a greater risk of MASLD.
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Affiliation(s)
- Nan Zhu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yongfeng Song
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chen Zhang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Kai Wang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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Sisto M, Lisi S. Immune and Non-Immune Inflammatory Cells Involved in Autoimmune Fibrosis: New Discoveries. J Clin Med 2023; 12:jcm12113801. [PMID: 37297996 DOI: 10.3390/jcm12113801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
Fibrosis is an important health problem and its pathogenetic activation is still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases, such as chronic inflammatory autoimmune diseases. Fibrotic tissue is always characterized by mononuclear immune cells infiltration. The cytokine profile of these cells shows clear proinflammatory and profibrotic characteristics. Furthermore, the production of inflammatory mediators by non-immune cells, in response to several stimuli, can be involved in the fibrotic process. It is now established that defects in the abilities of non-immune cells to mediate immune regulation may be involved in the pathogenicity of a series of inflammatory diseases. The convergence of several, not yet well identified, factors results in the aberrant activation of non-immune cells, such as epithelial cells, endothelial cells, and fibroblasts, that, by producing pro-inflammatory molecules, exacerbate the inflammatory condition leading to the excessive and chaotic secretion of extracellular matrix proteins. However, the precise cellular mechanisms involved in this process have not yet been fully elucidated. In this review, we explore the latest discoveries on the mechanisms that initiate and perpetuate the vicious circle of abnormal communications between immune and non-immune cells, responsible for fibrotic evolution of inflammatory autoimmune diseases.
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Affiliation(s)
- Margherita Sisto
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Sabrina Lisi
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari "Aldo Moro", 70124 Bari, Italy
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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19
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Bai YM, Yang F, Luo P, Xie LL, Chen JH, Guan YD, Zhou HC, Xu TF, Hao HW, Chen B, Zhao JH, Liang CL, Dai LY, Geng QS, Wang JG. Single-cell transcriptomic dissection of the cellular and molecular events underlying the triclosan-induced liver fibrosis in mice. Mil Med Res 2023; 10:7. [PMID: 36814339 PMCID: PMC9945401 DOI: 10.1186/s40779-023-00441-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 01/16/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage. METHODS C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing (scRNA-seq) was then carried out on TCS- or mock-treated mouse livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor (TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the molecular and cellular events after TCS exposure. To verify the TCS-induced liver fibrosis, the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson's trichrome and Sirius red staining. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies. RESULTS We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control group profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells (HSCs) were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition, other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interaction-mediated cellular communication in promoting liver fibrosis. CONCLUSIONS TCS modulates the cellular activities and fates of several specific cell types (including hepatocytes, HSCs, endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis. Overall, we provide the first comprehensive single-cell atlas of mouse livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.
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Affiliation(s)
- Yun-Meng Bai
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020 China
| | - Fan Yang
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632 China
| | - Piao Luo
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Lu-Lin Xie
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Jun-Hui Chen
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020 China
| | - Yu-Dong Guan
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Hong-Chao Zhou
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Teng-Fei Xu
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Hui-Wen Hao
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Bing Chen
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632 China
| | - Jia-Hui Zhao
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632 China
| | - Cai-Ling Liang
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Ling-Yun Dai
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020 China
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Qing-Shan Geng
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020 China
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
| | - Ji-Gang Wang
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020 China
- Department of Urology, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University Science and Technology, the Second Clinical Medical College, Jinan University, Shenzhen, 518020 China
- Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700 China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515 China
- Center for Reproductive Medicine, Dongguan Maternal and Child Health Care Hospital, Southern Medical University, Dongguan, 523125 Guangdong China
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20
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Oates JR, Sawada K, Giles DA, Alarcon PC, Damen MS, Szabo S, Stankiewicz TE, Moreno-Fernandez ME, Divanovic S. Thermoneutral housing shapes hepatic inflammation and damage in mouse models of non-alcoholic fatty liver disease. Front Immunol 2023; 14:1095132. [PMID: 36875069 PMCID: PMC9982161 DOI: 10.3389/fimmu.2023.1095132] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/27/2023] [Indexed: 02/19/2023] Open
Abstract
Introduction Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied. Methods Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice. Results We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score. Discussion Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression.
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Affiliation(s)
- Jarren R. Oates
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Daniel A. Giles
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Pablo C. Alarcon
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Michelle S.M.A. Damen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Sara Szabo
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Traci E. Stankiewicz
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Maria E. Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
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21
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Cannito S, Dianzani U, Parola M, Albano E, Sutti S. Inflammatory processes involved in NASH-related hepatocellular carcinoma. Biosci Rep 2023; 43:BSR20221271. [PMID: 36691794 PMCID: PMC9874450 DOI: 10.1042/bsr20221271] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/09/2022] [Accepted: 01/05/2023] [Indexed: 01/25/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the recent years nonalcoholic fatty liver disease (NAFLD) is becoming a growing cause of HCCs and the incidence of NAFLD-related HCCs is expected to further dramatically increase by the next decade. Chronic inflammation is regarded as the driving force of NAFLD progression and a key factor in hepatic carcinogenesis. Hepatic inflammation in NAFLD results from the persistent stimulation of innate immunity in response to hepatocellular injury and gut dysbiosis as well as by the activation of adaptive immunity. However, the relative roles of innate and adaptive immunity in the processes leading to HCC are still incompletely characterized. This is due to the complex interplay between different liver cell populations, which is also strongly influenced by gut-derived bacterial products, metabolic/nutritional signals. Furthermore, carcinogenic mechanisms in NAFLD/NASH appear to involve the activation of signals mediated by hypoxia inducible factors. This review discusses recent data regarding the contribution of different inflammatory cells to NAFLD-related HCC and their possible impact on patient response to current treatments.
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Affiliation(s)
- Stefania Cannito
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, Turin, Italy
| | - Umberto Dianzani
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of East Piedmont, Novara, Italy
| | - Maurizio Parola
- Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Turin, Turin, Italy
| | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of East Piedmont, Novara, Italy
| | - Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of East Piedmont, Novara, Italy
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22
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Kanemitsu-Okada K, Abe M, Nakamura Y, Miyake T, Watanabe T, Yoshida O, Koizumi Y, Hirooka M, Tokumoto Y, Matsuura B, Koizumi M, Hiasa Y. Role of B Cell-Activating Factor in Fibrosis Progression in a Murine Model of Non-Alcoholic Steatohepatitis. Int J Mol Sci 2023; 24:ijms24032509. [PMID: 36768854 PMCID: PMC9916461 DOI: 10.3390/ijms24032509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.
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23
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Sabotta CM, Kwan SY, Petty LE, Below JE, Joon A, Wei P, Fisher-Hoch SP, McCormick JB, Beretta L. Genetic variants associated with circulating liver injury markers in Mexican Americans, a population at risk for non-alcoholic fatty liver disease. Front Genet 2022; 13:995488. [PMID: 36386790 PMCID: PMC9644071 DOI: 10.3389/fgene.2022.995488] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 10/10/2022] [Indexed: 02/03/2023] Open
Abstract
Objective: Mexican Americans are disproportionally affected by non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma. Noninvasive means to identify those in this population at high risk for these diseases are urgently needed. Approach: The Cameron County Hispanic Cohort (CCHC) is a population-based cohort with high rates of obesity (51%), type 2 diabetes (28%) and NAFLD (49%). In a subgroup of 564 CCHC subjects, we evaluated 339 genetic variants previously reported to be associated with liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in United Kingdom and Japanese cohorts. Results: Association was confirmed for 86 variants. Among them, 27 had higher effect allele frequency in the CCHC than in the United Kingdom and Japanese cohorts, and 16 had stronger associations with AST and ALT than rs738409 (PNPLA3). These included rs17710008 (MYCT1), rs2519093 (ABO), rs1801690 (APOH), rs10409243 (S1PR2), rs1800759 (LOC100507053) and rs2491441 (RGL1), which were also associated with steatosis and/or liver fibrosis measured by vibration-controlled transient elastography. Main contributors to advanced fibrosis risk were rs11240351 (CNTN2), rs1800759 (LOC100507053), rs738409 (PNPLA3) and rs1801690 (APOH), with advanced fibrosis detected in 37.5% of subjects with 3 of these 4 variants [AOR = 11.6 (95% CI) = 3.8-35.3]. AST- and ALT-associated variants implicated distinct pathways (ethanol and galactose degradation versus antigen presentation and B cell development). Finally, 8 variants, including rs62292950 (DNAJC13), were associated with gut microbiome changes. Conclusion: These genotype-phenotype findings may have utility in risk modeling and disease prevention in this high-risk population.
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Affiliation(s)
- Caroline M. Sabotta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Suet-Ying Kwan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Lauren E. Petty
- Vanderbilt Genetics Institute and Department of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jennifer E. Below
- Vanderbilt Genetics Institute and Department of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Aron Joon
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Susan P. Fisher-Hoch
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, TX, United States
| | - Joseph B. McCormick
- School of Public Health, University of Texas Health Science Center at Houston, Brownsville Regional Campus, Brownsville, TX, United States
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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24
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Role of B Lymphocytes in the Pathogenesis of NAFLD: A 2022 Update. Int J Mol Sci 2022; 23:ijms232012376. [PMID: 36293233 PMCID: PMC9603875 DOI: 10.3390/ijms232012376] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
Non-alcoholic fatty liver disease and its related complications are becoming one of the most important health problems globally. The liver functions as both a metabolic and an immune organ. The crosstalk between hepatocytes and intrahepatic immune cells plays a key role in coordinating a dual function of the liver in terms of the protection of the host from antigenic overload as a result of receiving nutrients and gut microbiota antigenic stimulation via facilitating immunologic tolerance. B cells are the most abundant lymphocytes in the liver. The crucial role of intrahepatic B cells in energy metabolism under different immune conditions is now emerging in the literature. The accumulating evidence has demonstrated that the antibodies and cytokines produced by B cells in the microenvironment play key and distinct roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Herein, we have aimed to consolidate and update the current knowledge about the pathophysiological roles of B cells as well as the underlying mechanisms in energy metabolism. Understanding how B cells can exacerbate and suppress liver damage by exploiting the antibodies and cytokines they produce will be of great importance for designing B-cell targeting therapies to treat various liver diseases.
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25
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Zhang YL, Li ZJ, Gou HZ, Song XJ, Zhang L. The gut microbiota–bile acid axis: A potential therapeutic target for liver fibrosis. Front Cell Infect Microbiol 2022; 12:945368. [PMID: 36189347 PMCID: PMC9519863 DOI: 10.3389/fcimb.2022.945368] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/01/2022] [Indexed: 11/15/2022] Open
Abstract
Liver fibrosis involves the proliferation and deposition of extracellular matrix on liver tissues owing to various etiologies (including viral, alcohol, immune, and metabolic factors), ultimately leading to structural and functional abnormalities in the liver. If not effectively treated, liver fibrosis, a pivotal stage in the path to chronic liver disease, can progress to cirrhosis and eventually liver cancer; unfortunately, no specific clinical treatment for liver fibrosis has been established to date. In liver fibrosis cases, both the gut microbiota and bile acid metabolism are disrupted. As metabolites of the gut microbiota, bile acids have been linked to the progression of liver fibrosis via various pathways, thus implying that the gut microbiota–bile acid axis might play a critical role in the progression of liver fibrosis and could be a target for its reversal. Therefore, in this review, we examined the involvement of the gut microbiota–bile acid axis in liver fibrosis progression to the end of discovering new targets for the prevention, diagnosis, and therapy of chronic liver diseases, including liver fibrosis.
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Affiliation(s)
- Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Lei Zhang,
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26
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Sun R, Xiang Z, Wu B. T cells and liver fibrosis. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:125-132. [DOI: 10.1002/poh2.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/07/2022] [Indexed: 01/03/2025]
Abstract
AbstractLiver fibrosis develops from the excessive deposition of extracellular matrix in the liver caused by chronic liver inflammation or various chronic injuries, and it eventually develops into liver cirrhosis. The process of liver fibrosis is closely related to the immune response, and increasing evidence reveals the role of T lymphocytes, including Th1, Th2, Th17, regulatory T cells, and mucosa‐associated invariant T cells, in liver fibrosis. These immune cells play antifibrotic or profibrotic roles during fibrosis, and the reversal of fibrosis by targeting immune cells has attracted widespread attention. Activation of hepatic stellate cells, which form the core of fibrosis, is regulated by various immune mediators, including various immune cells and their associated cytokines. Therefore, the mechanism of action elicited by each cell type must be further elucidated to provide a basis for the design of new therapeutic targets. The purpose of this review is to summarize the roles and mechanisms of T lymphocytes and their subsets in liver fibrosis and highlight the biomarkers and potential therapeutic targets associated with these cells.
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Affiliation(s)
- Ruonan Sun
- Department of Gastroenterology Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou Guangdong China
| | - Zheng Xiang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong China
| | - Bin Wu
- Department of Gastroenterology Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou Guangdong China
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27
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Exploring mechanisms of Chaihu-Shugan-San against liver fibrosis by integrated multi-omics and network pharmacology approach. Biosci Rep 2022; 42:231546. [PMID: 35791909 PMCID: PMC9301292 DOI: 10.1042/bsr20221030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/19/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022] Open
Abstract
Chaihu-Shugan-San (CHSGS), a noted traditional Chinese medicine formula, has been used as a complementary and alternative therapy for liver fibrosis. However, the antifibrotic mechanisms of CHSGS still remain unclear. Thus, we used network pharmacology approach in combination with single cell and bulk transcriptomics to elucidate the antifibrotic mechanisms of CHSGS. We first screened out 134 bioactive ingredients of CHSGS through the defined criteria. Then, 1,150 genes were predicted to be targets for CHSGS, while 625 liver fibrosis-associated genes were identified by single cell transcriptomics analysis. Next, 71 intersecting genes of CHSGS and liver fibrosis were defined as the therapeutic targets in CHSGS against liver fibrosis. Further, 21 core targets and 12 core ingredients of CHSGS against liver fibrosis were also identified. Meanwhile, enrichment analyses of core targets highlighted that the key mechanisms of CHSGS against liver fibrosis include modulation of inflammation responses, inhibition of angiogenesis, and regulation of ECM remodeling, of which the most important mechanism was the regulation of ECM remodeling. The molecular docking simulation validated strong binding affinity between the core targets and core ingredients. Furthermore, 62-gene signature may be used for determining the prognosis in cirrhotic patients based on the results of ssGSEA-Cox analysis. In conclusion, this study revealed the multiple pharmacological targets and therapeutic mechanisms of CHSGS against liver fibrosis, which may thus serve as an effective antifibrotic therapy. Meanwhile, CHSGS may improve survival of patients with liver cirrhosis by the interaction of 62-gene signature.
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Deletion of Mettl3 at the Pro-B Stage Marginally Affects B Cell Development and Profibrogenic Activity of B Cells in Liver Fibrosis. J Immunol Res 2022; 2022:8118577. [PMID: 35747688 PMCID: PMC9213183 DOI: 10.1155/2022/8118577] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 04/13/2022] [Accepted: 05/14/2022] [Indexed: 12/03/2022] Open
Abstract
N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells' proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.
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29
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Poulsen KL, Cajigas-Du Ross CK, Chaney JK, Nagy LE. Role of the chemokine system in liver fibrosis: a narrative review. DIGESTIVE MEDICINE RESEARCH 2022; 5:30. [PMID: 36339901 PMCID: PMC9632683 DOI: 10.21037/dmr-21-87] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Liver fibrosis is a disease with characteristics of an aberrant wound healing response. Fibrosis is commonly the end-stage for chronic liver diseases like alcohol-associated liver disease (ALD), metabolic-associated liver disease, viral hepatitis, and hepatic autoimmune disease. Innate immunity contributes to the progression of many diseases through multiple mechanisms including production of pro-inflammatory mediators, leukocyte infiltration and tissue injury. Chemokines and their receptors orchestrate accumulation and activation of immune cells in tissues and are associated with multiple liver diseases; however, much less is known about their potential roles in liver fibrosis. This is a narrative review of current knowledge of the relationship of chemokine biology to liver fibrosis with insights into potential future therapeutic opportunities that can be explored in the future. METHODS A comprehensive literature review was performed searching PubMed for relevant English studies and texts regarding chemokine biology, chronic liver disease and liver fibrosis published between 1993 and 2021. The review was written and constructed to detail the intriguing chemokine biology, the relation of chemokines to tissue injury and resolution, and identify areas of discovery for fibrosis treatment. KEY CONTENT AND FINDINGS Chemokines are implicated in many chronic liver diseases, regardless of etiology. Most of these diseases will progress to fibrosis without appropriate treatment. The contributions of chemokines to liver disease and fibrosis are diverse and include canonical roles of modulating hepatic inflammation as well as directly contributing to fibrosis via activation of hepatic stellate cells (HSCs). Limited clinical evidence suggests that targeting chemokines in certain liver diseases might provide a therapeutic benefit to patients with hepatic fibrosis. CONCLUSIONS The chemokine system of ligands and receptors is a complex network of inflammatory signals in nearly all diseases. The specific sources of chemokines and cellular targets lend unique pathophysiological consequences to chronic liver diseases and established fibrosis. Although most chemokines are pro-inflammatory and contribute to tissue injury, others likely aid in the resolution of established fibrosis. To date, very few targeted therapies exist for the chemokine system and liver disease and/or fibrosis, and further study could identify viable treatment options to improve outcomes in patients with end-stage liver disease.
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Affiliation(s)
- Kyle L. Poulsen
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Christina K. Cajigas-Du Ross
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Jarod K. Chaney
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Laura E. Nagy
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
- Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
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30
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Tao X, Zhang R, Du R, Yu T, Yang H, Li J, Wang Y, Liu Q, Zuo S, Wang X, Lazarus M, Zhou L, Wang B, Yu Y, Shen Y. EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model. J Exp Med 2022; 219:213141. [PMID: 35420633 DOI: 10.1084/jem.20212414] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/07/2022] [Accepted: 03/09/2022] [Indexed: 12/13/2022] Open
Abstract
Natural killer (NK) cells exhibit antifibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin E2 (PGE2) plays a dual role in innate and adaptive immunity. Here, we found that E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell-specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. Loss of EP3 selectively reduced the cytotoxicity of the CD27+CD11b+ double positive (DP) NK subset against activated HSCs. Mechanistically, deletion of EP3 impaired the adhesion and cytotoxicity of DP NK cells toward HSCs through modulation of Itga4-VCAM1 binding. EP3 upregulated Itga4 expression in NK cells through promoting Spic nuclear translocation via PKC-mediated phosphorylation of Spic at T191. Activation of EP3 by sulprostone alleviated CCL4-induced liver fibrosis in mice. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.
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Affiliation(s)
- Xixi Tao
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Rui Zhang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Ronglu Du
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Tingting Yu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Hui Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Jiwen Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Yuhong Wang
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Qian Liu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Shengkai Zuo
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xi Wang
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Michael Lazarus
- International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
| | - Ying Yu
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yujun Shen
- Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
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Bae J, Kim JE, Perumalsamy H, Park S, Kim Y, Jun DW, Yoon TH. Mass Cytometry Study on Hepatic Fibrosis and Its Drug-Induced Recovery Using Mouse Peripheral Blood Mononuclear Cells. Front Immunol 2022; 13:814030. [PMID: 35222390 PMCID: PMC8863676 DOI: 10.3389/fimmu.2022.814030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/03/2022] [Indexed: 01/10/2023] Open
Abstract
The number of patients with liver diseases has increased significantly with the progress of global industrialization. Hepatic fibrosis, one of the most common liver diseases diagnosed in many developed countries, occurs in response to chronic liver injury and is primarily driven by the development of inflammation. Earlier immunological studies have been focused on the importance of the innate immune response in the pathophysiology of steatohepatitis and fibrosis, but recently, it has also been reported that adaptive immunity, particularly B cells, plays an essential role in hepatic inflammation and fibrosis. However, despite recent data showing the importance of adaptive immunity, relatively little is known about the role of B cells in the pathogenesis of steatohepatitis fibrosis. In this study, a single-cell-based, high-dimensional mass cytometric investigation of the peripheral blood mononuclear cells collected from mice belonging to three groups [normal chow (NC), thioacetamide (TAA), and 11beta-HSD inhibitor drug] was conducted to further understand the pathogenesis of liver fibrosis through reliable noninvasive biomarkers. Firstly, major immune cell types and their population changes were qualitatively analyzed using UMAP dimensionality reduction and two-dimensional visualization technique combined with a conventional manual gating strategy. The population of B cells displayed a twofold increase in the TAA group compared to that in the NC group, which was recovered slightly after treatment with the 11beta-HSD inhibitor drug. In contrast, the populations of NK cells, effector CD4+ T cells, and memory CD8+ T cells were significantly reduced in the TAA group compared with those in the NC group. Further identification and quantification of the major immune cell types and their subsets were conducted based on automated clustering approaches [PhenoGraph (PG) and FlowSOM]. The B-cell subset corresponding to PhenoGraph cluster PG#2 (CD62LhighCD44highLy6chigh B cells) and PG#3 (CD62LhighCD44highLy6clow B cell) appears to play a major role in both the development of hepatic fibrosis and recovery via treatment, whereas PG#1 (CD62LlowCD44highLy6clow B cell) seems to play a dominant role in the development of hepatic fibrosis. These findings provide insights into the roles of cellular subsets of B cells during the progression of, and recovery from, hepatic fibrosis.
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Affiliation(s)
- Jiwon Bae
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea
| | - Ji Eun Kim
- Department of Internal Medicine, Hanyang University Hospital, Seoul, South Korea
| | - Haribalan Perumalsamy
- Research Institute for Convergence of Basic Science, Hanyang University, Seoul, South Korea
| | - Sehee Park
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea
| | - Yun Kim
- Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul, South Korea.,Department of Clinical Pharmacology and Therapeutics, Hanyang University Hospital, Seoul, South Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Seoul, South Korea.,Hanyang Medicine-Engineering-Bio Collaborative & Comprehensive Center for Drug Development, Hanyang University, Seoul, South Korea.,Department of Medical and Digital Engineering, College of Engineering, Hanyang University, Seoul, South Korea
| | - Tae Hyun Yoon
- Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, South Korea.,Research Institute for Convergence of Basic Science, Hanyang University, Seoul, South Korea.,Institute of Next Generation Material Design, Hanyang University, Seoul, South Korea.,Yoon Idea Lab. Co. Ltd, Seoul, South Korea
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Ramadori P, Kam S, Heikenwalder M. T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis. Hepatology 2022; 75:1038-1049. [PMID: 35023202 DOI: 10.1002/hep.32336] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/20/2022]
Abstract
In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. However, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy. In this article, we will review the specific functions of several T-cell populations involved in NAFLD and NAFLD-driven HCC. We will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality. Finally, we will present the pros and cons of the current therapeutic strategies against NAFLD-related HCC and delineate possible novel approaches for the future.
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Affiliation(s)
- Pierluigi Ramadori
- Division of Chronic Inflammation and CancerGerman Center for Cancer Research (DKFZ)HeidelbergGermany
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Moog MT, Hinze C, Bormann T, Aschenbrenner F, Knudsen L, DeLuca DS, Jonigk D, Neubert L, Welte T, Gauldie J, Kolb M, Maus UA. B Cells Are Not Involved in the Regulation of Adenoviral TGF-β1- or Bleomycin-Induced Lung Fibrosis in Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1259-1271. [PMID: 35149532 DOI: 10.4049/jimmunol.2100767] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 12/27/2021] [Indexed: 06/14/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is an irreversible, age-related diffuse parenchymal lung disease of poorly defined etiology. Many patients with IPF demonstrate distinctive lymphocytic interstitial infiltrations within remodeled lung tissue with uncertain pathogenetic relevance. Histopathological examination of explant lung tissue of patients with IPF revealed accentuated lymphoplasmacellular accumulations in close vicinity to, or even infiltrating, remodeled lung tissue. Similarly, we found significant accumulations of B cells interfused with T cells within remodeled lung tissue in two murine models of adenoviral TGF-β1 or bleomycin (BLM)-induced lung fibrosis. Such B cell accumulations coincided with significantly increased lung collagen deposition, lung histopathology, and worsened lung function in wild-type (WT) mice. Surprisingly, B cell-deficient µMT knockout mice exhibited similar lung tissue remodeling and worsened lung function upon either AdTGF-β1 or BLM as for WT mice. Comparative transcriptomic profiling of sorted B cells collected from lungs of AdTGF-β1- and BLM-exposed WT mice identified a large set of commonly regulated genes, but with significant enrichment observed for Gene Ontology terms apparently not related to lung fibrogenesis. Collectively, although we observed B cell accumulations in lungs of IPF patients as well as two experimental models of lung fibrosis, comparative profiling of characteristic features of lung fibrosis between WT and B cell-deficient mice did not support a major involvement of B cells in lung fibrogenesis in mice.
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Affiliation(s)
- Marie T Moog
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | - Christopher Hinze
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | - Tina Bormann
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | | | - Lars Knudsen
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - David S DeLuca
- German Center for Lung Research, partner site Biomedical Research in Endstage and Obstructive Lung Disease Hanover, Hannover, Germany
| | - Danny Jonigk
- German Center for Lung Research, partner site Biomedical Research in Endstage and Obstructive Lung Disease Hanover, Hannover, Germany
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Lavinia Neubert
- German Center for Lung Research, partner site Biomedical Research in Endstage and Obstructive Lung Disease Hanover, Hannover, Germany
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Tobias Welte
- German Center for Lung Research, partner site Biomedical Research in Endstage and Obstructive Lung Disease Hanover, Hannover, Germany
- Clinic for Pneumology, Hannover Medical School, Hannover, Germany; and
| | - Jack Gauldie
- Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Martin Kolb
- Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Ulrich A Maus
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany;
- German Center for Lung Research, partner site Biomedical Research in Endstage and Obstructive Lung Disease Hanover, Hannover, Germany
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Singh Rawat B, Venkataraman R, Budhwar R, Tailor P. Methionine- and Choline-Deficient Diet Identifies an Essential Role for DNA Methylation in Plasmacytoid Dendritic Cell Biology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:881-897. [PMID: 35101891 DOI: 10.4049/jimmunol.2100763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/02/2021] [Indexed: 06/14/2023]
Abstract
Diet plays an important role in lifestyle disorders associated with the disturbed immune system. During the study of methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease, we observed a specific decrease in the plasmacytoid dendritic cell (pDC) fraction from murine spleens. While delineating the role for individual components, we identified that l-methionine supplementation correlates with representation of the pDC fraction. S-adenosylmethionine (SAM) is a key methyl donor, and we demonstrate that supplementation of methionine-deficient medium with SAM but not homocysteine reverses the defect in pDC development. l-Methionine has been implicated in maintenance of methylation status in the cell. Based on our observed effect of SAM and zebularine on DC subset development, we sought to clarify the role of DNA methylation in pDC biology. Whole-genome bisulfite sequencing analysis from the splenic DC subsets identified that pDCs display differentially hypermethylated regions in comparison with classical DC (cDC) subsets, whereas cDC1 and cDC2 exhibited comparable methylated regions, serving as a control in our study. We validated differentially methylated regions in the sorted pDC, CD8α+ cDC1, and CD4+ cDC2 subsets from spleens as well as FL-BMDC cultures. Upon analysis of genes linked with differentially methylated regions, we identified that differential DNA methylation is associated with the MAPK pathway such that its inhibition guides DC development toward the pDC subtype. Overall, our study identifies an important role for methionine in pDC biology.
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Affiliation(s)
| | - Ramya Venkataraman
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India
| | - Roli Budhwar
- Bionivid Technology Private Ltd., Bengaluru, Karnataka, India; and
| | - Prafullakumar Tailor
- Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India;
- Special Centre for Systems Medicine, Jawaharlal Nehru University, New Delhi, India
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SantaCruz-Calvo S, Bharath L, Pugh G, SantaCruz-Calvo L, Lenin RR, Lutshumba J, Liu R, Bachstetter AD, Zhu B, Nikolajczyk BS. Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities. Nat Rev Endocrinol 2022; 18:23-42. [PMID: 34703027 PMCID: PMC11005058 DOI: 10.1038/s41574-021-00575-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2021] [Indexed: 02/07/2023]
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.
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Affiliation(s)
- Sara SantaCruz-Calvo
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.
| | - Leena Bharath
- Department of Nutrition and Public Health, Merrimack College, North Andover, MA, USA
| | - Gabriella Pugh
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA
| | - Lucia SantaCruz-Calvo
- Department of Chemistry and Food Technology, Technical University of Madrid, Madrid, Spain
| | - Raji Rajesh Lenin
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA
| | - Jenny Lutshumba
- Department of Neuroscience, University of Kentucky, Lexington, KY, USA
| | - Rui Liu
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA
| | | | - Beibei Zhu
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA
| | - Barbara S Nikolajczyk
- Department of Pharmacology and Nutritional Sciences and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, KY, USA.
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Barrow F, Khan S, Wang H, Revelo XS. The Emerging Role of B Cells in the Pathogenesis of NAFLD. Hepatology 2021; 74:2277-2286. [PMID: 33961302 PMCID: PMC8463421 DOI: 10.1002/hep.31889] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/30/2021] [Accepted: 04/26/2021] [Indexed: 12/19/2022]
Abstract
NAFLD is one of the leading causes of abnormal liver function worldwide. NAFLD refers to a group of liver conditions ranging from nonalcoholic fatty liver to NASH, which involves inflammation, hepatocellular damage, and fibrosis. Triggering of inflammation in NASH is a key event in the progression of the disease, and identifying the factors that initiate or dysregulate this process is needed to develop strategies for its prevention or treatment. B cells have been implicated in several autoimmune and inflammatory diseases. However, their role in the pathogenesis of NAFLD and NASH is less clear. This review discusses the emerging evidence implicating intrahepatic B cells in the progression of NAFLD. We highlight the potential mechanisms of B-cell activation during NAFLD, such as increased hepatic expression of B-cell-activating factor, augmented oxidative stress, and translocation of gut-derived microbial products. We discuss the possible effector functions by which B cells promote NAFLD, including the production of proinflammatory cytokines and regulation of intrahepatic T cells and macrophages. Finally, we highlight the role of regulatory and IgA+ B cells in the pathogenesis of NASH-associated HCC. In this review, we make the case that future research is needed to investigate the potential of B-cell-targeting strategies for the treatment of NAFLD.
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Affiliation(s)
- Fanta Barrow
- Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisMN
| | - Saad Khan
- Department of ImmunologyUniversity of TorontoTorontoONCanada
| | - Haiguang Wang
- Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisMN
| | - Xavier S. Revelo
- Department of Integrative Biology and PhysiologyUniversity of MinnesotaMinneapolisMN,Center for ImmunologyUniversity of MinnesotaMinneapolisMN
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Jia F, Hu X, Kimura T, Tanaka N. Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies. Int J Mol Sci 2021; 22:10303. [PMID: 34638640 PMCID: PMC8508674 DOI: 10.3390/ijms221910303] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis.
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Affiliation(s)
- Fangping Jia
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
| | - Xiao Hu
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang 050017, China;
| | - Takefumi Kimura
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
- International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan
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Patel AM, Liu YS, Davies SP, Brown RM, Kelly DA, Scheel-Toellner D, Reynolds GM, Stamataki Z. The Role of B Cells in Adult and Paediatric Liver Injury. Front Immunol 2021; 12:729143. [PMID: 34630404 PMCID: PMC8495195 DOI: 10.3389/fimmu.2021.729143] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
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Affiliation(s)
- Arzoo M. Patel
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Yuxin S. Liu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Scott P. Davies
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rachel M. Brown
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Deirdre A. Kelly
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Dagmar Scheel-Toellner
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Gary M. Reynolds
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Barrow F, Khan S, Fredrickson G, Wang H, Dietsche K, Parthiban P, Robert S, Kaiser T, Winer S, Herman A, Adeyi O, Mouzaki M, Khoruts A, Hogquist KA, Staley C, Winer DA, Revelo XS. Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH Through Innate and Adaptive Signaling. Hepatology 2021; 74:704-722. [PMID: 33609303 PMCID: PMC8377092 DOI: 10.1002/hep.31755] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 12/21/2020] [Accepted: 01/08/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic steatohepatitis is rapidly becoming the leading cause of liver failure and indication for liver transplantation. Hepatic inflammation is a key feature of NASH but the immune pathways involved in this process are poorly understood. B lymphocytes are cells of the adaptive immune system that are critical regulators of immune responses. However, the role of B cells in the pathogenesis of NASH and the potential mechanisms leading to their activation in the liver are unclear. APPROACH AND RESULTS In this study, we report that NASH livers accumulate B cells with elevated pro-inflammatory cytokine secretion and antigen-presentation ability. Single-cell and bulk RNA sequencing of intrahepatic B cells from mice with NASH unveiled a transcriptional landscape that reflects their pro-inflammatory function. Accordingly, B-cell deficiency ameliorated NASH progression, and adoptively transferring B cells from NASH livers recapitulates the disease. Mechanistically, B-cell activation during NASH involves signaling through the innate adaptor myeloid differentiation primary response protein 88 (MyD88) as B cell-specific deletion of MyD88 reduced hepatic T cell-mediated inflammation and fibrosis, but not steatosis. In addition, activation of intrahepatic B cells implicates B cell-receptor signaling, delineating a synergy between innate and adaptive mechanisms of antigen recognition. Furthermore, fecal microbiota transplantation of human NAFLD gut microbiotas into recipient mice promoted the progression of NASH by increasing the accumulation and activation of intrahepatic B cells, suggesting that gut microbial factors drive the pathogenic function of B cells during NASH. CONCLUSION Our findings reveal that a gut microbiota-driven activation of intrahepatic B cells leads to hepatic inflammation and fibrosis during the progression of NASH through innate and adaptive immune mechanisms.
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Affiliation(s)
- Fanta Barrow
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Saad Khan
- Departments of Immunology and Laboratory Medicine & PathobiologyUniversity of TorontoTorontoONCanada.,Division of Cellular & Molecular BiologyToronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada
| | - Gavin Fredrickson
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Haiguang Wang
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Katrina Dietsche
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Preethy Parthiban
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Sacha Robert
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN
| | - Thomas Kaiser
- Department of SurgeryUniversity of MinnesotaMinneapolisMN
| | - Shawn Winer
- Departments of Immunology and Laboratory Medicine & PathobiologyUniversity of TorontoTorontoONCanada
| | - Adam Herman
- Minnesota Supercomputing InstituteUniversity of MinnesotaMinneapolisMN
| | - Oyedele Adeyi
- Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisMN
| | | | - Alexander Khoruts
- Division of Gastroenterology, Hepatology, and NutritionDepartment of MedicineUniversity of MinnesotaMinneapolisMN.,Center for ImmunologyUniversity of MinnesotaMinneapolisMN
| | - Kristin A Hogquist
- Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisMN.,Center for ImmunologyUniversity of MinnesotaMinneapolisMN
| | | | - Daniel A Winer
- Departments of Immunology and Laboratory Medicine & PathobiologyUniversity of TorontoTorontoONCanada.,Division of Cellular & Molecular BiologyToronto General Hospital Research InstituteUniversity Health NetworkTorontoONCanada.,Buck Institute for Research on AgingNovatoCA
| | - Xavier S Revelo
- Department of Integrative Biology & PhysiologyUniversity of Minnesota Medical SchoolMinneapolisMN.,Center for ImmunologyUniversity of MinnesotaMinneapolisMN
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40
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Cross-talk between hepatic stellate cells and T lymphocytes in liver fibrosis. Hepatobiliary Pancreat Dis Int 2021; 20:207-214. [PMID: 33972160 DOI: 10.1016/j.hbpd.2021.04.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Fibrosis results from inflammation and healing following injury. The imbalance between extracellular matrix (ECM) secretion and degradation leads to the ECM accumulation and liver fibrosis. This process is regulated by immune cells. T lymphocytes, including alpha beta (αβ) T cells, which have adaptive immune functions, and gamma delta (γδ) T cells, which have innate immune functions, are considered regulators of liver fibrosis. This review aimed to present the current understanding of the cross-talk between T lymphocytes and hepatic stellate cells (HSCs), which are the key cells in liver fibrosis. DATA SOURCES The keywords "liver fibrosis", "immune", and "T cells" were used to retrieve articles published in PubMed database before January 31, 2020. RESULTS The ratio of CD8+ (suppressor) T cells to CD4+ (helper) T cells is significantly higher in the liver than in the peripheral blood. T cells secrete a series of cytokines and chemokines to regulate the inflammation in the liver and the activation of HSCs to influence the course of liver fibrosis. In addition, HSCs also regulate the differentiation and proliferation of T cells. CONCLUSIONS The cross-talk between T cells and HSCs regulates liver fibrosis progression. The elucidation of this communication process will help us to understand the pathological process of liver fibrosis.
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Chung Y, Rahim MN, Graham JJ, Zen Y, Heneghan MA. An update on the pharmacological management of autoimmune hepatitis. Expert Opin Pharmacother 2021; 22:1475-1488. [PMID: 33624559 DOI: 10.1080/14656566.2021.1895747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Autoimmune hepatitis (AIH) is an immune mediated, inflammatory disease affecting the liver as a result of environmental triggers in susceptible individuals leading to loss of self-tolerance. The immunopathogenesis of AIH is not fully understood, which limits targeted therapeutic options.Areas covered: In this review, the authors provide an overview of current practice in the management of AIH, which include induction therapy with corticosteroids (± thiopurines), followed by maintenance therapy. Lack of early response to treatment may serve as a predictor of those at risk of requiring treatment escalation to second- and third-line agents such as mycophenolate mofetil (MMF), calcineurin inhibitors or biologics. Evidence for third-line agents from small retrospective studies or individual centers are reviewed. The nuances of AIH treatment in pregnancy, overlap syndromes, and drug induced liver injury (DILI) warrant further consideration.Expert opinion: Augmenting the balance of regulatory T cells (Treg) and effector T cells is an appealing therapeutic target with a multitude of agents in development. Many of the challenges in AIH research are due to its rarity and lack of randomized data. Management of AIH should strive towards individualized care through risk stratification and use of the best therapeutic modality for each patient.
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Affiliation(s)
- Yooyun Chung
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Jonathon J Graham
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, United Kingdom
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Zeng F, Zhang Y, Han X, Zeng M, Gao Y, Weng J. Predicting Non-Alcoholic Fatty Liver Disease Progression and Immune Deregulations by Specific Gene Expression Patterns. Front Immunol 2021; 11:609900. [PMID: 33574818 PMCID: PMC7870871 DOI: 10.3389/fimmu.2020.609900] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide with rising rates in parallel to obesity, type 2 diabetes, and metabolic syndrome. NAFLD includes pathologies ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis and cirrhosis (NASH), which may eventually develop into hepatocellular carcinoma (HCC). Mechanically, lipids accumulation and insulin resistance act as the first hit, inflammation and fibrosis serve as the second hit. Currently, the diagnosis of NAFLD mainly depends on pathology examination and medical imaging, whereas proper gene signature classifiers are necessary for the evaluation of disease status. Here, we developed three signature classifiers to distinguish different NAFLD disease states (NAFL and NASH). Moreover, we found that B cells, DCs, and MAIT cells are key deregulated immune cells in NAFLD, which are associated with NAFLD and NAFLD-HCC progression. Meanwhile, AKR1B10 and SPP1 are closely related to the above three immune cell infiltrations and immunosuppressive cytokines expressions in NAFLD and NAFLD-HCC. Subsequently, we screened out AKR1B10 and SPP1 sensitive molecules TGX-221, which may provide a possible therapy for NAFLD and NAFLD-HCC.
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Affiliation(s)
- Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Min Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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Mo F, Luo Y, Yan Y, Li J, Lai S, Wu W. Are activated B cells involved in the process of myocardial fibrosis after acute myocardial infarction? An in vivo experiment. BMC Cardiovasc Disord 2021; 21:5. [PMID: 33407160 PMCID: PMC7789158 DOI: 10.1186/s12872-020-01775-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/08/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammatory cells infiltrate into the ischemic and hypoxic myocardial tissue after myocardial infarction. B cells gather at the site of myocardial injury and secrete cytokines to regulate immune inflammation and fiber repair processes. METHODS The animal experiment used ligation of the left anterior descending (LAD) artery of C57BL/6 mice to establish a mouse acute myocardial infarction (AMI) model to observe changes in activated B cells and cytokines at different time points. Twelve-week-old C57BL/6 male mice were randomly divided into the Sham group (24 mice) (thread under the LAD artery without ligation) and the AMI group (64 mice). In addition, C57BL/6 B-cell knockout (BKO) mice and C57BL/6 wild-type (WT) mice were used to establish AMI models to observe the expression levels of cardiomyocyte cytokines, such as TNF-α IL-1β, IL-6, TGF-β1, COL1-A1, COL3-AIII, TIMP, and MMP9. Moreover, pathological and collagen changes in the myocardium were analysed. One-way ANOVA and LSD method was used for comparisons of multiple and pairwise groups respectively. P < 0.05 indicated significant differences. RESULTS An AMI model of C57BL/6 mice was established successfully. The ratio of activated B cells and the expression of TNF-α, IL-1β, IL-6, TGF-β1, and B cell activating factor (BAFF) in the 5-day subgroup were the highest in the myocardium, spleen and peripheral blood with the most obvious myocardial inflammatory cell infiltration. The cytokines mRNA expression levels in the 5-day subgroup of the BKO group were decreased compared with those in the WT group (P < 0.05). Among the 2-week subgroups of the Sham, WT and BKO groups, the the LVEDd and LVESd of the BKO group were lower than those of the WT group (P < 0.05), and the left ventricular ejection fraction was higher than that of the WT group (P < 0.05). CONCLUSION Activated B cells participate in the sustained state of myocardial inflammation and immune system activation after AMI, and may affect the metabolism of myocardial collagen after AMI by secreting cytokines. Moreover, B cells promote the expression of myocardial collagen Type I and Type III and damage the left ventricular ejection function.
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Affiliation(s)
- Fanrui Mo
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, China
- Department of Cardiology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China
| | - Ying Luo
- Guangxi Medical University, Nanning, China
| | - Yuluan Yan
- Department of Cardiology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China
| | - Juan Li
- Department of Cardiology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China
| | - Shayi Lai
- Department of Cardiology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China
| | - Weifeng Wu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, China.
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Loss of natural resistance to schistosome in T cell deficient rat. PLoS Negl Trop Dis 2020; 14:e0008909. [PMID: 33347431 PMCID: PMC7785244 DOI: 10.1371/journal.pntd.0008909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 01/05/2021] [Accepted: 10/21/2020] [Indexed: 01/08/2023] Open
Abstract
Schistosomiasis is among the major neglected tropical diseases and effective prevention by boosting the immune system is still not available. T cells are key cellular components governing adaptive immune response to various infections. While common laboratory mice, such as C57BL/6, are highly susceptible to schistosomiasis, the SD rats are extremely resistant. However, whether adaptive immunity is necessary for such natural resistance to schistosomiasis in rats remains to be determined. Therefore, it is necessary to establish genetic model deficient in T cells and adaptive immunity on the resistant SD background, and to characterize liver pathology during schistosomiasis. In this study we compared experimental schistosomiasis in highly susceptible C57BL/6 (B6) mice and in resistant SD rats, using cercariae of Schistosoma japonicum. We observed a marked T cell expansion in the spleen of infected B6 mice, but not resistant SD rats. Interestingly, CD3e−/− B6 mice in which T cells are completely absent, the infectious burden of adult worms was significantly higher than that in WT mice, suggesting an anti-parasitic role for T cells in B6 mice during schistosome infection. In further experiments, we established Lck deficient SD rats by using CRISPR/Cas9 in which T cell development was completely abolished. Strikingly, we found that such Lck deficiency in SD rats severely impaired their natural resistance to schistosome infection, and fostered parasite growth. Together with an additional genetic model deficient in T cells, the CD3e−/− SD rats, we confirmed the absence of T cell resulted in loss of natural resistance to schistosome infection, but also mitigated liver immunopathology. Our further experiments showed that regulatory T cell differentiation in infected SD rats was significantly decreased during schistosomiasis, in contrast to significant increase of regulatory T cells in infected B6 mice. These data suggest that T cell mediated immune tolerance facilitates persistent infection in mice but not in SD rats. The demonstration of an important role for T cells in natural resistance of SD rats to schistosomiasis provides experimental evidences supporting the rationale to boost T cell responses in humans to prevent and treat schistosomiasis. Schistosomiasis is among the major neglected tropical diseases and affects mainly the developing countries. Although the role of the immune system in driving immunopathology in schistosomiasis has been extensively studied, how adaptive immunity contributes to disease resistance during schistosome infection is still not completely understood. Most livestock species as well as humans are susceptible to schistosomiasis, while some mammals are extremely resistant. The common laboratory C57BL/6 mice are highly susceptible to schistosomiasis; however, the SD rats are extremely resistant. In this study, we first used T cell deficient CD3e−/− C57BL/6 mice and experimental Schistosoma japonicum infection and further established novel T cell deficient models in SD rats to assess anti-parasite roles of T cells. Strikingly, we found that the natural resistance of SD rat to schistosomiasis was abolished in the absence of T cells, despite the fact that the liver pathology was mitigated following infection. Therefore, our study presented experimental support for the rationale to boost T cell function for clearance of schistosome parasites.
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Liang Q, Zhang M, Hu Y, Zhang W, Zhu P, Chen Y, Xue P, Li Q, Wang K. Gut Microbiome Contributes to Liver Fibrosis Impact on T Cell Receptor Immune Repertoire. Front Microbiol 2020; 11:571847. [PMID: 33329430 PMCID: PMC7729130 DOI: 10.3389/fmicb.2020.571847] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/05/2020] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota (GM) modifies the intrahepatic immune microenvironment, but the underlying mechanisms remain poorly understood. Liver fibrosis-associated imprinting is predicted to be reflected in GM. This study investigated the link between GM and the intrahepatic T cell receptor (TCR) immune repertoire (IR), and whether GM modulates the intrahepatic immune microenvironment via TCR IR during liver fibrosis. We analyzed the correlation between GM and TCR IR during liver fibrogenesis. Accordingly, 16S rRNA gene sequencing (16S-seq) and bulk immune repertoire sequencing (IR-seq) were performed to characterize GM and intrahepatic TCR IR. Fecal microbial transplant (FMT) and TCRβ knockout (TcrbKO) mouse models were employed to determine the biological link between GM and TCR IR in liver fibrosis. We found that GM and intrahepatic TCR IR are highly correlated, with both showing reduced diversity and centralized distribution during liver fibrosis. The restoration of normal intestinal microbiota may reshape intrahepatic TCR IR and delay liver fibrosis. Interestingly, TCR IR ablation abrogated the impact of GM on liver fibrogenesis. Furthermore, GM modulated hepatic stellate cell (HSC) activation via TCR IR-mediated intrahepatic immune milieu. Our study demonstrates that GM, which exhibits cross-talk with the intrahepatic TCR IR, influences the intrahepatic immune microenvironment and liver fibrosis progression.
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Affiliation(s)
- Qing Liang
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Meina Zhang
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Yudi Hu
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Wei Zhang
- Department of Pathology, The 971 Hospital of People's Liberation Army Navy, Qingdao, China
| | - Ping Zhu
- Department of Gynecology and Obstetrics, The 971 Hospital of People's Liberation Army Navy, Qingdao, China
| | - Yujie Chen
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Pengxin Xue
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Qiyuan Li
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
| | - Kejia Wang
- National Institute for Data Science in Health and Medicine, School of Medicine, Xiamen University, Xiamen, China
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Azad AI, Krishnan A, Troop L, Li Y, Katsumi T, Pavelko K, Kostallari E, Guicciardi ME, Gores GJ. Targeted Apoptosis of Ductular Reactive Cells Reduces Hepatic Fibrosis in a Mouse Model of Cholestasis. Hepatology 2020; 72:1013-1028. [PMID: 32128842 PMCID: PMC7774262 DOI: 10.1002/hep.31211] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/03/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS In cholestatic liver diseases, ductular reactive (DR) cells extend into the hepatic parenchyma and promote inflammation and fibrosis. We have previously observed that multidrug-resistant 2 (Mdr2-/- ) double knockout (DKO) mice lacking tumor necrosis factor-related apoptosis-inducing ligand receptor (Tr-/- ) display a more extensive ductular reaction and hepatic fibrosis compared to Mdr2-/- mice. This observation suggests that the magnitude of the DR-cell population may be regulated by apoptosis. APPROACH AND RESULTS To examine this concept, we cultured epithelial cell adhesion molecule-positive reactive cholangioids (ERCs) obtained from wild-type (WT), Tr-/- , Mdr2-/- and DKO mice. Single-cell transcriptomics and immunostaining of both WT and DKO ERCs confirmed their DR-cell phenotype. Moreover, DKO ERCs displayed a unique translational cluster with expression of chemokines, indicating a reactive state. Incubation with the myeloid cell leukemia 1 (MCL1) inhibitor S63845, a proapoptotic BH3-mimetic therapy, significantly decreased DKO and Mdr2-/- ERC viability compared to WT. Intravenous administration of S63845 significantly reduced the DR-cell population and markers of inflammation and liver fibrosis in Mdr2-/- and DKO mice. Furthermore, DKO mice treated with S63845 displayed a significant decrease in hepatic B lymphocytes compared to untreated mice as assessed by high-definition mass cytometry by time-of-flight. Coculture of bone marrow-derived macrophages with ERCs from DKO mouse livers up-regulated expression of the B cell-directed chemokine (C-C motif) ligand 5. Finally, DR cells were noted to be primed for apoptosis with Bcl-2 homologous antagonist/killer activation in vitro and in vivo in primary sclerosing cholangitis liver specimens. CONCLUSIONS DR cells appear to play a key role in recruiting immune cells to the liver to actively create an inflammatory and profibrogenic microenvironment. Pharmacologic targeting of MCL1 in a mouse model of chronic cholestasis reduces DR-cell and B-cell populations and hepatic fibrosis.
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Affiliation(s)
- Adiba I. Azad
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Anuradha Krishnan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Leia Troop
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Ying Li
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Tomohiro Katsumi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Kevin Pavelko
- Department of Immunology, Mayo Clinic, Rochester, MN
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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Ramachandran P, Matchett KP, Dobie R, Wilson-Kanamori JR, Henderson NC. Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis. Nat Rev Gastroenterol Hepatol 2020; 17:457-472. [PMID: 32483353 DOI: 10.1038/s41575-020-0304-x] [Citation(s) in RCA: 164] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/08/2020] [Indexed: 12/19/2022]
Abstract
Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.
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Affiliation(s)
- Prakash Ramachandran
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Kylie P Matchett
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Ross Dobie
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - John R Wilson-Kanamori
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. .,MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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Jürgensen HJ, van Putten S, Nørregaard KS, Bugge TH, Engelholm LH, Behrendt N, Madsen DH. Cellular uptake of collagens and implications for immune cell regulation in disease. Cell Mol Life Sci 2020; 77:3161-3176. [PMID: 32100084 PMCID: PMC11105017 DOI: 10.1007/s00018-020-03481-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 12/15/2022]
Abstract
As the dominant constituent of the extracellular matrix (ECM), collagens of different types are critical for the structural properties of tissues and make up scaffolds for cellular adhesion and migration. Importantly, collagens also directly modulate the phenotypic state of cells by transmitting signals that influence proliferation, differentiation, polarization, survival, and more, to cells of mesenchymal, epithelial, or endothelial origin. Recently, the potential of collagens to provide immune regulatory signals has also been demonstrated, and it is believed that pathological changes in the ECM shape immune cell phenotype. Collagens are themselves heavily regulated by a multitude of structural modulations or by catabolic pathways. One of these pathways involves a cellular uptake of collagens or soluble collagen-like defense collagens of the innate immune system mediated by endocytic collagen receptors. This cellular uptake is followed by the degradation of collagens in lysosomes. The potential of this pathway to regulate collagens in pathological conditions is evident from the increased extracellular accumulation of both collagens and collagen-like defense collagens following endocytic collagen receptor ablation. Here, we review how endocytic collagen receptors regulate collagen turnover during physiological conditions and in pathological conditions, such as fibrosis and cancer. Furthermore, we highlight the potential of collagens to regulate immune cells and discuss how endocytic collagen receptors can directly regulate immune cell activity in pathological conditions or do it indirectly by altering the extracellular milieu. Finally, we discuss the potential collagen receptors utilized by immune cells to directly detect ECM-related changes in the tissues which they encounter.
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Affiliation(s)
- Henrik J Jürgensen
- Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark.
| | - Sander van Putten
- Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark
| | - Kirstine S Nørregaard
- Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark
| | - Thomas H Bugge
- Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Lars H Engelholm
- Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark
| | - Niels Behrendt
- Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center, University of Copenhagen, Ole Maaloesvej 5, 2200, Copenhagen N, Denmark
| | - Daniel H Madsen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730, Herlev, Denmark.
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Madill-Thomsen K, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, Foroncewicz B, Francis I, Grąt M, Jurczyk K, Klintmalm G, Krasnodębski M, McCaughan G, Miquel R, Montano-Loza A, Moonka D, Mucha K, Myślak M, Pączek L, Perkowska-Ptasińska A, Piecha G, Reichman T, Sanchez-Fueyo A, Tronina O, Wawrzynowicz-Syczewska M, Więcek A, Zieniewicz K, Halloran PF. The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study. Am J Transplant 2020; 20:2156-2172. [PMID: 32090446 DOI: 10.1111/ajt.15828] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 02/07/2020] [Accepted: 02/09/2020] [Indexed: 01/25/2023]
Abstract
Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1normal " (N = 129), T cell-mediated rejection (TCMR) "R2TCMR " (N = 37), early injury "R3injury " (N = 61), and fibrosis "R4late " (N = 8). Groups differed in median time posttransplant, for example, R3injury 99 days vs R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR , R3injury , and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.
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Affiliation(s)
| | | | - Chandra Bhati
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Michał Ciszek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Sandy Feng
- University of California San Francisco, San Francisco, California, USA
| | - Bartosz Foroncewicz
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Jurczyk
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | | | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Geoff McCaughan
- Centenary Research Institute, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, The University of Sydney, Sydney, NSW, Australia
| | | | | | | | - Krzysztof Mucha
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marek Myślak
- Department of Clinical Interventions, Department of Nephrology and Kidney, Transplantation, SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | | | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | | | | | - Olga Tronina
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada
- University of Alberta, Edmonton, Alberta, Canada
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Huang E, Peng N, Xiao F, Hu D, Wang X, Lu L. The Roles of Immune Cells in the Pathogenesis of Fibrosis. Int J Mol Sci 2020; 21:E5203. [PMID: 32708044 PMCID: PMC7432671 DOI: 10.3390/ijms21155203] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/15/2022] Open
Abstract
Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.
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Affiliation(s)
- Enyu Huang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Na Peng
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Fan Xiao
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Dajun Hu
- Department of Rheumatology and Immunology, the Second People’s Hospital of Three Gorges University, Yichang 443000, China; (N.P.); (D.H.)
| | - Xiaohui Wang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China; (E.H.); (F.X.)
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