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Chen X, Wu C, Tang F, Zhou J, Mo L, Li Y, He J. The Immune Microenvironment: New Therapeutic Implications in Organ Fibrosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e05067. [PMID: 40391706 DOI: 10.1002/advs.202505067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/28/2025] [Indexed: 05/22/2025]
Abstract
Fibrosis, characterized by abnormal deposition of structural proteins, is a major cause of tissue dysfunction in chronic diseases. The disease burden associated with progressive fibrosis is substantial, and currently approved drugs are unable to effectively reverse it. Immune cells are increasingly recognized as crucial regulators in the pathological process of fibrosis by releasing effector molecules, such as cytokines, chemokines, extracellular vesicles, metabolites, proteases, or intercellular contact. Therefore, targeting the immune microenvironment can be a potential strategy for fibrosis reduction and reversion. This review summarizes the recent advances in the understanding of the immune microenvironment in fibrosis including phenotypic and functional transformations of immune cells and the interaction of immune cells with other cells. The novel opportunities for the discovery and development of drugs for immune microenvironment remodeling and their associated challenges are also discussed.
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Affiliation(s)
- Xiangqi Chen
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuan Wu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fei Tang
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jingyue Zhou
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Mo
- Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
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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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Vizioli G, Nicoletti A, Feliciani D, Funaro B, Zileri Dal Verme L, Ponziani FR, Zocco MA, Gasbarrini A, Gabrielli M. Immunotherapy and MASLD-Related HCC: Should We Reconsider the Role of Etiology in the Therapeutic Approach to HCC? APPLIED SCIENCES 2025; 15:2279. [DOI: 10.3390/app15052279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and typically arises in the context of chronic liver disease. With the increasing prevalence of metabolic disorders, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease and the most rapidly increasing cause of HCC. The role of dysfunctional innate and adaptive immune responses in the development and progression of HCC is well-established, prompting numerous trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) in targeting tumor cells. These trials have yielded promising results, and ICIs, in combination with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, are now approved as first-line therapy for patients with metastatic or unresectable HCC, irrespective of the underlying liver disease. Notably, MASLD itself is characterized by immune system dysfunction, as metabolic inflammation plays a central role in its onset and progression. However, clinical studies and post-hoc analyses suggest that immunotherapy may be less effective in MASLD-associated HCC compared to viral-related HCC. This emerging evidence raises the question of whether the underlying liver disease influences the therapeutic response to ICIs in HCC. It may be time to consider tailoring therapeutic strategies for HCC based on the specific etiological, histological, and genotypical subgroups.
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Affiliation(s)
- Giuseppina Vizioli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alberto Nicoletti
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Daniela Feliciani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Barbara Funaro
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maurizio Gabrielli
- Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Cai H, Zhang J, Chen C, Shen J, Zhang X, Peng W, Li C, Lv H, Wen T. Prognostic assessment of early-stage liver cirrhosis induced by HCV using an integrated model of CX3CR1-associated immune infiltration genes. Sci Rep 2025; 15:1771. [PMID: 39800763 PMCID: PMC11725579 DOI: 10.1038/s41598-024-80422-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 11/19/2024] [Indexed: 01/16/2025] Open
Abstract
Chemokine (C-X3-C motif) Receptor 1 (CX3CR1) primarily mediates the chemotaxis and adhesion of immune cells. However, its role in hepatitis C virus (HCV)-induced early-stage liver cirrhosis remains unexplored. GSE15654 was downloaded from the GEO database. The Cox regression model, CIBERSORT, and LASSO technique were utilized to identify CX3CR1-associated immune infiltration genes (IIGs). Surgical resection samples were collected for verification, including 3 healthy controls (HC), 4 individuals with HCV-induced hepatic cirrhosis, and 3 with HCV-induced liver failure. High CX3CR1 expression correlated with worse prognosis in early-stage cirrhosis. CX3CR1-associated IIGs, namely ACTIN4, CD1E, TMCO1, and WSF1, were identified, showing specific expression in the livers of individuals with post-hepatic cirrhosis and liver failure compared to HC. LOC400499 and MTHFD2 were elevated in individuals with liver failure in comparison to those with hepatocirrhosis. Notably, high infiltration of plasma cells and low infiltration of monocytes were predictive of poor prognosis in early-stage cirrhosis. The combined risk model predicted that high expression of CX3CR1-associated IIGs and increased infiltration of plasma cells were associated with unfavorable prognosis in individuals with HCV-induced early-stage liver cirrhosis. The developed combined risk model effectively predicted the prognosis of these individuals.
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Affiliation(s)
- Haozheng Cai
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, 610041, China
| | - Jing Zhang
- Division of Biliary Tract, Department of General Surgery, West China Hospital, Si Chuan University, Chengdu, China
| | - Chuwen Chen
- 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 Z, Yuan Z, Wang Y, Zhang YH, Li Q, Zeng X, Guan Z, Bahabayi A, Wang P, Liu C. Upregulation of granzyme B and C-X3-C motif receptor 1 in circulating plasmablasts was negatively regulated by Notch signal in patients with systemic lupus erythematosus. J Leukoc Biol 2024; 116:1061-1071. [PMID: 38833584 DOI: 10.1093/jleuko/qiae127] [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: 09/27/2023] [Revised: 03/31/2024] [Accepted: 06/01/2024] [Indexed: 06/06/2024] Open
Abstract
As one molecule related to cytotoxicity, surface expression of C-X3-C motif receptor 1 (CX3CR1) was highly correlated with intracellular granzyme B (GZMB) in natural killer and cytolytic T cells. However, the expression of CX3CR1 and GZMB in B cells has not been clarified, and their clinical significance in systemic lupus erythematosus (SLE) remains unclear. This study aimed to clarify the changes and clinical significance of peripheral blood B cells expressing GZMB and/or CX3CR1 in SLE. Peripheral blood was collected from 39 patients with SLE and 48 healthy controls. We found that GZMB and CX3CR1 expression varied in different B-cell subsets, with plasmablasts possessing the highest positive percentages, consistent with bioinformatics prediction. GZMB+ and CX3CR1+ percentages in circulating B cells and plasmablasts were increased in patients with SLE. CX3CR1 was upregulated on B cells after in vitro stimulation. Notch intracellular domain expression was significantly decreased in plasmablasts of patients with SLE, and CX3CR1 in plasmablasts was downregulated with the addition of JAG1. In conclusion, GZMB and CX3CR1 were increased in B cells and in plasmablasts of patients with SLE and CX3CR1 was negatively regulated by Notch signal in plasmablasts, which may be involved in SLE pathogenesis.
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Affiliation(s)
- Zhonghui Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
| | - Zihang Yuan
- School of Basic Medical Sciences, Peking University Health Science Center, 38# Xueyuan Road, Beijing 100191, China
| | - Yiying Wang
- School of Basic Medical Sciences, Peking University Health Science Center, 38# Xueyuan Road, Beijing 100191, China
| | - Ya-Hui Zhang
- School of Basic Medical Sciences, Peking University Health Science Center, 38# Xueyuan Road, Beijing 100191, China
| | - Qi Li
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
| | - Xingyue Zeng
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
| | - Zhao Guan
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
| | - Ayibaota Bahabayi
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
| | - Pingzhang Wang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, 38# Xueyuan Road, Beijing 100191, China
- Peking University Center for Human Disease Genomics, Peking University Health Science Center, 38# Xueyuan Road, Beijing 100191, China
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People's Hospital, 11# Xizhimen South Street, Beijing 100044, China
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Chen X, Yang Y, Sun S, Liu Q, Yang Y, Jiang L. CX3C chemokine: Hallmarks of fibrosis and ageing. Pharmacol Res 2024; 208:107348. [PMID: 39134186 DOI: 10.1016/j.phrs.2024.107348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/03/2024] [Accepted: 08/07/2024] [Indexed: 08/18/2024]
Abstract
Fibrosis refers to the progressive tissue lesion process characterized by excessive secretion and deposition of extracellular matrix (ECM). Abnormal fibrous tissue deposition distorts tissue architecture and leads to the progressive loss of organ function. Notably, fibrosis is one of the primary pathological appearances of many end stage illnesses, and is considered as a lethal threat to human health, especially in the elderly with ageing-related diseases. CX3C ligand 1 (CX3CL1) is the only member of chemokine CX3C and binds specifically to CX3C receptor 1 (CX3CR1). Different from other chemokines, CX3CL1 possesses both chemotactic and adhesive activity. CX3CL1/CX3CR1 axis involves in various physiological and pathological processes, and exerts a critical role in cells from the immune system, vascular system, and nervous system etc. Notably, increasing evidence has demonstrated that CX3CL1/CX3CR1 signaling pathway is closely related to the pathological process of fibrosis in multiple tissue and organs. We reviewed the crucial role of CX3CL1/CX3CR1 axis in fibrosis and ageing and systematically summarized the underlying mechanism, which offers prospective strategies of targeting CX3C for the therapy of fibrosis and ageing-related diseases.
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Affiliation(s)
- Xuanning Chen
- School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai 200011, China
| | - Yiling Yang
- Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China
| | - Siyuan Sun
- Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China
| | - Qiong Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China.
| | - Lingyong Jiang
- Center of Craniofacial Orthodontics, Department of Oral and Cranio-maxillofacial Science, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Disease, Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China.
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Wang B, Yang L, Yuan X, Zhang Y. Roles and therapeutic targeting of dendritic cells in liver fibrosis. J Drug Target 2024; 32:647-654. [PMID: 38682473 DOI: 10.1080/1061186x.2024.2347365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 04/18/2024] [Indexed: 05/01/2024]
Abstract
Liver fibrosis is a common pathological condition marked by excessive accumulation of extracellular matrix proteins, resulting in irreversible cirrhosis and cancer. Dendritic cells (DCs) act as the crucial component of hepatic immunity and are believed to affect fibrosis by regulating the proliferation and differentiation of hepatic stellate cells (HSCs), a key mediator of fibrogenesis, and by interplaying with immune cells in the liver. This review concisely describes the process of fibrogenesis, and the phenotypic and functional characteristics of DCs in the liver. Besides, it focuses on the interaction between DCs and HSCs, T cells, and natural killer (NK) cells, as well as the dual roles of DCs in liver fibrosis, for the sake of exploring the potential of targeting DCs as a therapeutic strategy for the disease.
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Affiliation(s)
- Bingyu Wang
- Heilongjiang University of Chinese Medicine, Harbin, P.R. China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, P.R. China
| | - Liuxin Yang
- Heilongjiang University of Chinese Medicine, Harbin, P.R. China
| | - Xingxing Yuan
- Heilongjiang University of Chinese Medicine, Harbin, P.R. China
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, P.R. China
| | - Yang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, P.R. China
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Mao X, Larsen SB, Zachariassen LSF, Brunse A, Adamberg S, Mejia JLC, Larsen F, Adamberg K, Nielsen DS, Hansen AK, Hansen CHF, Rasmussen TS. Transfer of modified gut viromes improves symptoms associated with metabolic syndrome in obese male mice. Nat Commun 2024; 15:4704. [PMID: 38830845 PMCID: PMC11148109 DOI: 10.1038/s41467-024-49152-w] [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: 06/30/2023] [Accepted: 05/24/2024] [Indexed: 06/05/2024] Open
Abstract
Metabolic syndrome encompasses amongst other conditions like obesity and type-2 diabetes and is associated with gut microbiome (GM) dysbiosis. Fecal microbiota transplantation (FMT) has been explored to treat metabolic syndrome by restoring the GM; however, concerns on accidentally transferring pathogenic microbes remain. As a safer alternative, fecal virome transplantation (FVT, sterile-filtrated feces) has the advantage over FMT in that mainly bacteriophages are transferred. FVT from lean male donors have shown promise in alleviating the metabolic effects of high-fat diet in a preclinical mouse study. However, FVT still carries the risk of eukaryotic viral infections. To address this, recently developed methods are applied for removing or inactivating eukaryotic viruses in the viral component of FVT. Modified FVTs are compared with unmodified FVT and saline in a diet-induced obesity model on male C57BL/6 N mice. Contrasted with obese control, mice administered a modified FVT (nearly depleted for eukaryotic viruses) exhibits enhanced blood glucose clearance but not weight loss. The unmodified FVT improves liver pathology and reduces the proportions of immune cells in the adipose tissue with a non-uniform response. GM analysis suggests that bacteriophage-mediated GM modulation influences outcomes. Optimizing these approaches could lead to the development of safe bacteriophage-based therapies targeting metabolic syndrome through GM restoration.
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Affiliation(s)
- Xiaotian Mao
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark
| | - Sabina Birgitte Larsen
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark
| | - Line Sidsel Fisker Zachariassen
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Anders Brunse
- Section of Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Signe Adamberg
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Josue Leonardo Castro Mejia
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark
| | - Frej Larsen
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark
| | - Kaarel Adamberg
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Dennis Sandris Nielsen
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark
| | - Axel Kornerup Hansen
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Camilla Hartmann Friis Hansen
- Section of Preclinical Disease Biology, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Torben Sølbeck Rasmussen
- Section of Food Microbiology, Gut Health, and Fermentation, Department of Food Science, University of Copenhagen, Frederiksberg, Denmark.
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Szukiewicz D. CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis. Int J Mol Sci 2024; 25:4679. [PMID: 38731899 PMCID: PMC11083509 DOI: 10.3390/ijms25094679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and strongly attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine release, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis, and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals.
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Affiliation(s)
- Dariusz Szukiewicz
- Department of Biophysics, Physiology & Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, 02-004 Warsaw, Poland
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10
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Mao S, Wang X, Li M, Liu H, Liang H. The role and mechanism of hydrogen sulfide in liver fibrosis. Nitric Oxide 2024; 145:41-48. [PMID: 38360133 DOI: 10.1016/j.niox.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/20/2024] [Accepted: 02/12/2024] [Indexed: 02/17/2024]
Abstract
Hydrogen sulfide (H2S) is the third new gas signaling molecule in the human body after the discovery of NO and CO. Similar to NO, it has the functions of vasodilation, anti-inflammatory, antioxidant, and regulation of cell formation. Enzymes that can produce endogenous H2S, such as CSE, CSB, and 3-MST, are common in liver tissues and are important regulatory molecules in the liver. In the development of liver fibrosis, H2S concentration and expression of related enzymes change significantly, which makes it possible to use exogenous gases to treat liver diseases. This review summarizes the role of H2S in liver fibrosis and its complications induced by NAFLD and CCl4, and elaborates on the anti-liver fibrosis effect of H2S through the mechanism of reducing oxidative stress, inhibiting inflammation, regulating autophagy, regulating glucose and lipid metabolism, providing theoretical reference for further research on the treatment of liver fibrosis with H2S.
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Affiliation(s)
- Shaoyu Mao
- Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xuemei Wang
- Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Miaoqing Li
- Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hanshu Liu
- Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hongxia Liang
- Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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11
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Li R, Zhao M, Miao C, Shi X, Lu J. Identification and validation of key biomarkers associated with macrophages in nonalcoholic fatty liver disease based on hdWGCNA and machine learning. Aging (Albany NY) 2023; 15:15451-15472. [PMID: 38147020 PMCID: PMC10781485 DOI: 10.18632/aging.205374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 11/21/2023] [Indexed: 12/27/2023]
Abstract
BACKGROUND NAFLD has attracted increasing attention because of its high prevalence and risk of progression to cirrhosis or even hepatocellular carcinoma. Therefore, research into the root causes and molecular indicators of NAFLD is crucial. METHODS We analyzed scRNA-seq data and RNA-seq data from normal and NAFLD liver samples. We utilized hdWGCNA to find module-related genes associated with the phenotype. Multiple machine learning algorithms were used to validate the model diagnostics and further screen for genes that are characteristic of NAFLD. The NAFLD mouse model was constructed using the MCD diet to validate the diagnostic effect of the genes. RESULTS We identified a specific macrophage population called NASH-macrophages by single-cell sequencing analysis. Cell communication analysis and Pseudo-time trajectory analysis revealed the specific role and temporal distribution of NASH-macrophages in NAFLD. The hdWGCNA screening yielded 30 genes associated with NASH-macrophages, and machine learning algorithms screened and obtained two genes characterizing NAFLD. The immune infiltration indicated that these genes were highly associated with macrophages. Notably, we verified by RT-qPCR, IHC, and WB that MAFB and CX3CR1 are highly expressed in the MCD mouse model and may play important roles. CONCLUSIONS Our study revealed a macrophage population that is closely associated with NAFLD. Using hdWGCNA analysis and multiple machine learning algorithms, we identified two NAFLD signature genes that are highly correlated with macrophages. Our findings may provide potential feature markers and therapeutic targets for NAFLD.
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Affiliation(s)
- Ruowen Li
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Mingjian Zhao
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Chengxu Miao
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Xiaojia Shi
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
| | - Jinghui Lu
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
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12
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Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023; 35:1852-1871. [PMID: 37939656 PMCID: PMC10680147 DOI: 10.1016/j.cmet.2023.10.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
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Affiliation(s)
- Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Hak Chung
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Samir Softic
- Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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13
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Zhang C, Sui Y, Liu S, Yang M. Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. EXPLORATION OF DIGESTIVE DISEASES 2023:246-275. [DOI: https:/doi.org/10.37349/edd.2023.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/05/2023] [Indexed: 11/27/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, Shanxi Province, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
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14
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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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15
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Lurje I, Gaisa NT, Weiskirchen R, Tacke F. Mechanisms of organ fibrosis: Emerging concepts and implications for novel treatment strategies. Mol Aspects Med 2023; 92:101191. [PMID: 37236017 DOI: 10.1016/j.mam.2023.101191] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023]
Abstract
Fibrosis, or tissue scarring, develops as a pathological deviation from the physiological wound healing response and can occur in various organs such as the heart, lung, liver, kidney, skin, and bone marrow. Organ fibrosis significantly contributes to global morbidity and mortality. A broad spectrum of etiologies can cause fibrosis, including acute and chronic ischemia, hypertension, chronic viral infection (e.g., viral hepatitis), environmental exposure (e.g., pneumoconiosis, alcohol, nutrition, smoking) and genetic diseases (e.g., cystic fibrosis, alpha-1-antitrypsin deficiency). Common mechanisms across organs and disease etiologies involve a sustained injury to parenchymal cells that triggers a wound healing response, which becomes deregulated in the disease process. A transformation of resting fibroblasts into myofibroblasts with excessive extracellular matrix production constitutes the hallmark of disease, however, multiple other cell types such as immune cells, predominantly monocytes/macrophages, endothelial cells, and parenchymal cells form a complex network of profibrotic cellular crosstalk. Across organs, leading mediators include growth factors like transforming growth factor-β and platelet-derived growth factor, cytokines like interleukin-10, interleukin-13, interleukin-17, and danger-associated molecular patterns. More recently, insights into fibrosis regression and resolution of chronic conditions have deepened our understanding of beneficial, protective effects of immune cells, soluble mediators and intracellular signaling. Further in-depth insights into the mechanisms of fibrogenesis can provide the rationale for therapeutic interventions and the development of targeted antifibrotic agents. This review gives insight into shared responses and cellular mechanisms across organs and etiologies, aiming to paint a comprehensive picture of fibrotic diseases in both experimental settings and in human pathology.
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Affiliation(s)
- Isabella Lurje
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Nadine T Gaisa
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University Hospital, Aachen, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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16
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Lendoiro-Cino N, Rodríguez-Coello A, Saborido A, F-Burguera E, Fernández-Rodríguez JA, Meijide-Faílde R, Blanco FJ, Vaamonde-García C. Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance. J Physiol Biochem 2023:10.1007/s13105-023-00968-y. [PMID: 37335394 DOI: 10.1007/s13105-023-00968-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/31/2023] [Indexed: 06/21/2023]
Abstract
Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology.
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Affiliation(s)
- Natalia Lendoiro-Cino
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Arianna Rodríguez-Coello
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Anna Saborido
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Elena F-Burguera
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
- Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
| | - Jennifer A Fernández-Rodríguez
- Grupo Envejecimiento e Inflamación, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Rosa Meijide-Faílde
- Grupo de Terapia Celular y Medicina Regenerativa, Centro Interdisciplinar de Química e Bioloxía (CICA), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Ciencias da Saúde, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Francisco J Blanco
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain
- Grupo de Investigación en Reumatología y Salud, Centro Interdisciplinar de Química e Bioloxía (CICA), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Universidade da Coruña (UDC), 15006, A Coruña, Spain
| | - Carlos Vaamonde-García
- Grupo de Investigación en Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006, A Coruña, Spain.
- Grupo de Investigación en Reumatología y Salud, Centro Interdisciplinar de Química e Bioloxía (CICA), Departamento de Bioloxía, Facultad de Ciencias, Universidade da Coruña (UDC), 15008, A Coruña, Spain.
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17
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Li Y, Zhao L, Sun C, Yang J, Zhang X, Dou S, Hua Q, Ma A, Cai J. Regulation of Gut Microflora by Lactobacillus casei Zhang Attenuates Liver Injury in Mice Caused by Anti-Tuberculosis Drugs. Int J Mol Sci 2023; 24:ijms24119444. [PMID: 37298396 DOI: 10.3390/ijms24119444] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 05/24/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
The gut-liver axis may provide a new perspective for treating anti-tuberculosis drug-induced liver injury (ATDILI). Herein, the protective effect of Lactobacillus casei (Lc) was investigated by modulating gut microflora (GM) and the toll like receptor 4 (TLR4)-nuclear factor (NF)-κB-myeloiddifferentiationfactor 88 (MyD88) pathway. C57BL/6J mice were given three levels of Lc intragastrically for 2 h before administering isoniazid and rifampicin for 8 weeks. Blood, liver, and colon tissues, as well as cecal contents, were collected for biochemical and histological examination, as well as Western blot, quantitative real time polymerase chain reaction (qRT-PCR), and 16S rRNA analyses. Lc intervention decreased alkaline phosphatase (ALP), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and tumor necrosis factor (TNF)-α levels (p < 0.05), recovered hepatic lobules, and reduced hepatocyte necrosis to alleviate liver injury induced by anti-tuberculosis drugs. Moreover, Lc also increased the abundance of Lactobacillus and Desulfovibrio and decreased Bilophila abundance, while enhancing zona occludens (ZO)-1 and claudin-1 protein expression compared with the model group (p < 0.05). Furthermore, Lc pretreatment reduced the lipopolysaccharide (LPS) level and downregulated NF-κB and MyD88 protein expression (p < 0.05), thus restraining pathway activation. Spearman correlation analysis indicated that Lactobacillus and Desulfovibrio were positively correlated with ZO-1 or occludin protein expression and negatively correlated with pathway protein expression. Desulfovibrio had significant negative relationships with alanine aminotransferase (ALT) and LPS levels. In contrast, Bilophila had negative associations with ZO-1, occludin, and claudin-1 protein expressions and positive correlations with LPS and pathway proteins. The results prove that Lactobacillus casei can enhance the intestinal barrier and change the composition of the gut microflora. Moreover, Lactobacillus casei may also inhibit TLR4-NF-κB-MyD88 pathway activation and alleviate ATDILI.
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Affiliation(s)
- Yue Li
- School of Public Health, Qingdao University, Qingdao 266021, China
- Institute of Nutrition and Health, Qingdao University, Qingdao 266021, China
| | - Liangjie Zhao
- School of Public Health, Qingdao University, Qingdao 266021, China
- Institute of Nutrition and Health, Qingdao University, Qingdao 266021, China
| | - Changyu Sun
- School of Public Health, Qingdao University, Qingdao 266021, China
| | - Jingyi Yang
- School of Public Health, Qingdao University, Qingdao 266021, China
| | - Xinyue Zhang
- School of Public Health, Qingdao University, Qingdao 266021, China
| | - Sheng Dou
- School of Public Health, Qingdao University, Qingdao 266021, China
| | - Qinglian Hua
- School of Public Health, Qingdao University, Qingdao 266021, China
- Institute of Nutrition and Health, Qingdao University, Qingdao 266021, China
| | - Aiguo Ma
- School of Public Health, Qingdao University, Qingdao 266021, China
- Institute of Nutrition and Health, Qingdao University, Qingdao 266021, China
| | - Jing Cai
- School of Public Health, Qingdao University, Qingdao 266021, China
- Institute of Nutrition and Health, Qingdao University, Qingdao 266021, China
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18
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Ma DW, Ha J, Yoon KS, Kang I, Choi TG, Kim SS. Innate Immune System in the Pathogenesis of Non-Alcoholic Fatty Liver Disease. Nutrients 2023; 15:2068. [PMID: 37432213 DOI: 10.3390/nu15092068] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/17/2023] [Accepted: 04/21/2023] [Indexed: 07/12/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by lipid accumulation in hepatocytes with low alcohol consumption. The development of sterile inflammation, which occurs in response to a range of cellular stressors or injuries, has been identified as a major contributor to the pathogenesis of NAFLD. Recent studies of the pathogenesis of NAFLD reported the newly developed roles of damage-associated molecular patterns (DAMPs). These molecules activate pattern recognition receptors (PRRs), which are placed in the infiltrated neutrophils, dendritic cells, monocytes, or Kupffer cells. DAMPs cause the activation of PRRs, which triggers a number of immunological responses, including the generation of cytokines that promote inflammation and the localization of immune cells to the site of the damage. This review provides a comprehensive overview of the impact of DAMPs and PRRs on the development of NAFLD.
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Affiliation(s)
- Dae Won Ma
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Joohun Ha
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung Sik Yoon
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Tae Gyu Choi
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
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19
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Li HY, Fu SW, Wu JC, Li ZH, Xu MY. Vsig4 + resident single-Kupffer cells improve hepatic inflammation and fibrosis in NASH. Inflamm Res 2023; 72:669-682. [PMID: 36745210 DOI: 10.1007/s00011-023-01696-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 10/28/2022] [Accepted: 01/20/2023] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The role of macrophages in the pathogenesis of nonalcoholic steatohepatitis (NASH) is complex and unclear. METHODS Single-cell RNA sequencing was performed on nonparenchymal cells isolated from NASH and control mice. The expression of Vsig4+ macrophages was verified by qPCR, flow cytometry and immunohistochemistry. Primary hepatic macrophages were cocultured with primary hepatocytes or hepatic stellate cells (LX2) cells by Transwell to detect immunofluorescence and oil red O staining. RESULTS Two main single macrophage subsets were identified that exhibited a significant change in cell percentage when NASH occurred: resident Kupffer cells (KCs; Cluster 2) and lipid-associated macrophages (LAMs; Cluster 13). Nearly 82% of resident single KCs in Cluster 2 specifically expressed Cd163, and an inhibited subgroup of Cd163+ resident single-KCs was suggested to be protective against NASH. Similar to Cd163, Vsig4 was both enriched in and specific to Cluster 2. The percentage of Vsig4+-KCs was significantly decreased in NASH in vivo and in vitro. Hepatocytes and hepatic stellate cells produced less lipid droplet accumulation, proinflammatory protein (TNF-α) and profibrotic protein (α-SMA) in response to coculture with Vsig4+-KCs than in those cocultured with lipotoxic KCs. CONCLUSIONS A subgroup of Vsig4+ resident single-KCs was shown to improve hepatic inflammation and fibrosis in NASH.
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Affiliation(s)
- Hui-Yi Li
- Department of Gastroenterology, School of Medicine, Shanghai East Hospital, Tongji University, No. 1800, Yuntai Rd, Shanghai, 310115, China
| | - Seng-Wang Fu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Jun-Cheng Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000, Jiangsu Province, China
| | - Zheng-Hong Li
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Rd, Shanghai, 200092, China.
| | - Ming-Yi Xu
- Department of Gastroenterology, School of Medicine, Shanghai East Hospital, Tongji University, No. 1800, Yuntai Rd, Shanghai, 310115, China.
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20
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Wang GY, Zhang XY, Wang CJ, Guan YF. Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies. World J Gastroenterol 2023; 29:75-95. [PMID: 36683713 PMCID: PMC9850950 DOI: 10.3748/wjg.v29.i1.75] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/29/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a leading chronic disease worldwide, affects approximately a quarter of the global population. Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD and is more likely to progress to liver fibrosis than simple steatosis. NASH is also identified as the most rapidly growing cause of hepatocellular carcinoma. Although in the past decade, several phase II/III clinical trials have shown promising results in the use of novel drugs targeting lipid synthase, farnesoid X receptor signaling, peroxisome proliferator-activated receptor signaling, hepatocellular injury, and inflammatory signaling, proven pharmaceutical agents to treat NASH are still lacking. Thus, continuous exploration of the mechanism underlying the pathogenesis of NAFLD and the identification of novel therapeutic targets remain urgent tasks in the field. In the current review, we summarize studies reported in recent years that not only provide new insights into the mechanisms of NAFLD development but also explore the possibility of treating NAFLD by targeting newly identified signaling pathways. We also discuss evidence focusing on the intrahepatic targets involved in the pathogenesis of NAFLD as well as extrahepatic targets affecting liver metabolism and function.
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Affiliation(s)
- Guang-Yan Wang
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin 300070, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - Xiao-Yan Zhang
- Health Science Center, East China Normal University, Shanghai 200241, China
| | - Chun-Jiong Wang
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin 300070, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin 300070, China
| | - You-Fei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning Province, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning Province, China
- Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian 116044, Liaoning Province, China
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21
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Wang X, Wang Z, Liu B, Jin R, Song Y, Fei R, Cong X, Huang R, Li X, Yang J, Wei L, Rao H, Liu F. Characteristic gene expression in the liver monocyte-macrophage-DC system is associated with the progression of fibrosis in NASH. Front Immunol 2023; 14:1098056. [PMID: 36911682 PMCID: PMC9998489 DOI: 10.3389/fimmu.2023.1098056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/06/2023] [Indexed: 02/26/2023] Open
Abstract
Background The monocyte-macrophage-dendritic cell (DC) (MMD) system exerts crucial functions that may modulate fibrogenesis in nonalcoholic steatohepatitis (NASH). In this study, we explored the cell characteristics, distribution and developmental trajectory of the liver MMD system in NASH mice with fibrosis and clarified characteristic genes of the MMD system involved in liver fibrosis progression in NASH mice and patients. Methods Single cells in liver tissue samples from NASH and normal mice were quantified using single-cell RNA sequencing (scRNA-seq) analysis. Differentially expressed genes (DEGs) in the MMD system by pseudotime analysis were validated by tyramide signal amplification (TSA)-immunohistochemical staining (IHC) and analyzed by second harmonic generation (SHG)/two-photon excitation fluorescence (TPEF). Results Compared with control mice, there were increased numbers of monocytes, Kupffer cells, and DCs in two NASH mouse models. From the transcriptional profiles of these single cells, we identified 8 monocyte subsets (Mono1-Mono8) with different molecular and functional properties. Furthermore, the pseudotime analysis showed that Mono5 and Mono6 were at the beginning of the trajectory path, whereas Mono2, Mono4, Kupffer cells and DCs were at a terminal state. Genes related to liver collagen production were at the late stage of this trajectory path. DEGs analysis revealed that the genes Fmnl1 and Myh9 in the MMD system were gradually upregulated during the trajectory. By TSA-IHC, the Fmnl1 and Myh9 expression levels were increased and associated with collagen production and fibrosis stage in NASH mice and patients. Conclusions Our transcriptome data provide a novel landscape of the MMD system that is involved in advanced NASH disease status. Fmnl1 and Myh9 expression in the MMD system was associated with the progression of NASH fibrosis.
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Affiliation(s)
- Xiaoxiao Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Zilong Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Baiyi Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Yuyun Song
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Ran Fei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xu Cong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xiaohe Li
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Jia Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Feng Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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22
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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23
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Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms232012202. [PMID: 36293058 PMCID: PMC9603526 DOI: 10.3390/ijms232012202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/30/2022] [Accepted: 10/09/2022] [Indexed: 11/17/2022] Open
Abstract
Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced.
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24
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Kandhi R, Variya B, Ramanathan S, Ilangumaran S. An improved method for isolation and flow cytometric characterization of intrahepatic leukocytes from fatty and fibrotic liver tissues. Anat Rec (Hoboken) 2022; 306:1011-1030. [PMID: 35848859 DOI: 10.1002/ar.25039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/28/2022] [Accepted: 06/28/2022] [Indexed: 12/11/2022]
Abstract
Flow cytometry is an imperative tool to characterize alterations in a wide range of immune cell populations during inflammatory conditions and disease states that affect the liver such as the obesity-induced non-alcoholic fatty liver disease and liver fibrosis. Identification and quantification of immune cell subsets from the liver is critically dependent on efficient isolation of intrahepatic leukocytes. The isolation of leukocytes from fatty and fibrotic livers and processing the cells for flow cytometry can be challenging with respect to cell yields, purity and most importantly, the level of autofluorescence resulting from fat deposition. Here, we describe an efficient method for isolating intrahepatic leukocytes from mice fed with high fat diet and propose a strategy to alleviate autofluorescence during phenotyping by multicolor flowcytometry. We also describe a gating strategy for robust identification of granulocytes, pro-inflammatory, anti-inflammatory and transitional state monocyte subsets, dendritic cells, B cell, T lymphocyte subpopulations and NK cell subsets. Overall, the procedures described here will allow simultaneous processing of several samples while ensuring reproducible cell isolation and efficient noise reduction required for reliable characterization of intrahepatic leukocytes from the fatty liver tissues.
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Affiliation(s)
- Rajani Kandhi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Bhavesh Variya
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada
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25
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Fiorucci S, Zampella A, Ricci P, Distrutti E, Biagioli M. Immunomodulatory functions of FXR. Mol Cell Endocrinol 2022; 551:111650. [PMID: 35472625 DOI: 10.1016/j.mce.2022.111650] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 02/08/2023]
Abstract
The Farnesoid-x-receptor (FXR) is a bile acids sensor activated in humans by primary bile acids. FXR is mostly expressed in liver, intestine and adrenal glands but also by cells of innate immunity, including macrophages, liver resident macrophages, the Kupffer cells, natural killer cells and dendritic cells. In normal physiology and clinical disorders, cells of innate immunity mediate communications between liver, intestine and adipose tissues. In addition to FXR, the G protein coupled receptor (GPBAR1), that is mainly activated by secondary bile acids, whose expression largely overlaps FXR, modulates chemical communications from the intestinal microbiota and the host's immune system, integrating epithelial cells and immune cells in the entero-hepatic system, providing a mechanism for development of a tolerogenic state toward the intestinal microbiota. Disruption of FXR results in generalized inflammation and disrupted bile acids metabolism. While FXR agonism in preclinical models provides counter-regulatory signals that attenuate inflammation-driven immune dysfunction in a variety of liver and intestinal disease models, the clinical relevance of these mechanisms in the setting of FXR-related disorders remain poorly defined.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy. http://www.gastroenterologia.unipg.it
| | - Angela Zampella
- University of Naples Federico II, Department of Pharmacy, Naples, Italy
| | - Patrizia Ricci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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26
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Gao Y, Zhang H, Wang Y, Han T, Jin J, Li J, Tang Y, Liu C. L-Cysteine Alleviates Myenteric Neuron Injury Induced by Intestinal Ischemia/Reperfusion via Inhibitin the Macrophage NLRP3-IL-1β Pathway. Front Pharmacol 2022; 13:899169. [PMID: 35754513 PMCID: PMC9213754 DOI: 10.3389/fphar.2022.899169] [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: 03/18/2022] [Accepted: 04/26/2022] [Indexed: 11/13/2022] Open
Abstract
Ischemia/reperfusion injury is a common pathophysiological process in the clinic. It causes various injuries, multiple organ dysfunction, and even death. There are several possible mechanisms about ischemia/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were used to establish the ischemia/reperfusion model in vivo. Peritoneal macrophages were used for ATP depletion and hypoxia/reoxygenation experiment in vitro. L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia/reperfusion led to the injury of myenteric neurons. From experiments in vitro and in vivo, we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1β. L-cysteine increased cystathionine beta synthase and H2S produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1β-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia/reperfusion injury.
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Affiliation(s)
- Yifei Gao
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Haojie Zhang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Yujin Wang
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Ting Han
- Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Jing Jin
- Department of TCM Rheumatology, China-Japan Friendship Hospital, Beijing, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China
| | - Yan Tang
- Department of Gastroenterology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Chuanyong Liu
- Department of Physiology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, China.,Provincial Key Lab of Mental Disorders, Shandong University, Jinan, China
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27
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An Update on the Chemokine System in the Development of NAFLD. Medicina (B Aires) 2022; 58:medicina58060761. [PMID: 35744024 PMCID: PMC9227560 DOI: 10.3390/medicina58060761] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Sustained hepatic inflammation is a key driver of the transition from simple fatty liver to nonalcoholic steatohepatitis (NASH), the more aggressive form of NAFLD. Hepatic inflammation is orchestrated by chemokines, a family of chemoattractant cytokines that are produced by hepatocytes, Kupffer cells (liver resident macrophages), hepatic stellate cells, endothelial cells, and vascular smooth muscle cells. Over the last three decades, accumulating evidence from both clinical and experimental investigations demonstrated that chemokines and their receptors are increased in the livers of NAFLD patients and that CC chemokine ligand (CCL) 2 and CCL5 in particular play a pivotal role in inducing insulin resistance, steatosis, inflammation, and fibrosis in liver disease. Cenicriviroc (CVC), a dual antagonist of these chemokines’ receptors, CCR2 and CCR5, has been tested in clinical trials in patients with NASH-associated liver fibrosis. Additionally, recent studies revealed that other chemokines, such as CCL3, CCL25, CX3C chemokine ligand 1 (CX3CL1), CXC chemokine ligand 1 (CXCL1), and CXCL16, can also contribute to the pathogenesis of NAFLD. Here, we review recent updates on the roles of chemokines in the development of NAFLD and their blockade as a potential therapeutic approach.
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28
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Chung KW, Cho YE, Kim SJ, Hwang S. Immune-related pathogenesis and therapeutic strategies of nonalcoholic steatohepatitis. Arch Pharm Res 2022; 45:229-244. [PMID: 35391713 DOI: 10.1007/s12272-022-01379-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/25/2022] [Indexed: 11/02/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and has become prevalent in the adult population worldwide, given the ongoing obesity pandemic. NAFLD comprises several hepatic disorders, ranging from fatty liver to nonalcoholic steatohepatitis (NASH), cirrhosis, and carcinoma. Excessive fat accumulation in the liver can induce the development of fatty liver, whereas the progression of fatty liver to NASH involves various complex factors. The crucial difference between fatty liver and NASH is the presence of inflammation and fibrosis, the emergence of which is closely associated with the action of immune cells and immunological factors, such as chemokines and cytokines. Thus, expanding our understanding of immunological mechanisms contributing to NASH pathogenesis will lead to the identification of therapeutic targets and the development of viable therapeutics against NASH.
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Affiliation(s)
- Ki Wung Chung
- Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Ye Eun Cho
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea
| | - Seung-Jin Kim
- Department of Biochemistry, College of Natural Sciences, Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, 24341, Republic of Korea.,Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Seonghwan Hwang
- Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
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29
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Xiang M, Liu T, Tian C, Ma K, Gou J, Huang R, Li S, Li Q, Xu C, Li L, Lee CH, Zhang Y. Kinsenoside attenuates liver fibro-inflammation by suppressing dendritic cells via the PI3K-AKT-FoxO1 pathway. Pharmacol Res 2022; 177:106092. [PMID: 35066108 PMCID: PMC8776354 DOI: 10.1016/j.phrs.2022.106092] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/16/2022] [Accepted: 01/18/2022] [Indexed: 12/25/2022]
Abstract
Kinsenoside (KD) exhibits anti-inflammatory and immunosuppressive effects. Dendritic cells (DCs) are critical regulators of the pathologic inflammatory milieu in liver fibrosis (LF). Herein, we explored whether and how KD repressed development of LF via DC regulation and verified the pathway involved in the process. Given our analysis, both KD and adoptive transfer of KD-conditioned DCs conspicuously reduced hepatic histopathological damage, proinflammatory cytokine release and extracellular matrix deposition in CCl4-induced LF mice. Of note, KD restrained the LF-driven rise in CD86, MHC-II, and CCR7 levels and, simultaneously, upregulated PD-L1 expression on DCs specifically, which blocked CD8+T cell activation. Additionally, KD reduced DC glycolysis, maintained DCs immature, accompanied by IL-12 decrease in DCs. Inhibiting DC function by KD disturbed the communication of DCs and HSCs with the expression or secretion of α-SMA and Col-I declined in the liver. Mechanistically, KD suppressed the phosphorylation of PI3K-AKT driven by LF or PI3K agonist, followed by enhanced nuclear transport of FoxO1 and upregulated interaction of FoxO1 with the PD-L1 promoter in DCs. PI3K inhibitor or si-IL-12 acting on DC could relieve LF, HSC activation and diminish the effect of KD. In conclusion, KD suppressed DC maturation with promoted PD-L1 expression via PI3K-AKT-FoxO1 and decreased IL-12 secretion, which blocked activation of CD8+T cells and HSCs, thereby alleviating liver injury and fibro-inflammation in LF.
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Affiliation(s)
- Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tingting Liu
- Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, the Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, Anhui, China
| | - Cheng Tian
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kun Ma
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Gou
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rongrong Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Senlin Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qing Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chuanrui Xu
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chih-Hao Lee
- Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA
| | - Yonghui Zhang
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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30
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Hong Y, Sheng L, Zhong J, Tao X, Zhu W, Ma J, Yan J, Zhao A, Zheng X, Wu G, Li B, Han B, Ding K, Zheng N, Jia W, Li H. Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, attenuates nonalcoholic fatty liver disease in mice. Gut Microbes 2021; 13:1-20. [PMID: 34125646 PMCID: PMC8205104 DOI: 10.1080/19490976.2021.1930874] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The emerging evidence supports the use of prebiotics like herb-derived polysaccharides for treating nonalcoholic fatty liver disease (NAFLD) by modulating gut microbiome. The present study was initiated on the microbiota-dependent anti-NAFLD effect of Astragalus polysaccharides (APS) extracted from Astragalus mongholicus Bunge in high-fat diet (HFD)-fed mice. However, the exact mechanisms underlying the beneficial effects of APS on NAFLD formation remain poorly understood.Co-housing experiment was used to assess the microbiota dependent anti-NAFLD effect of APS. Then, targeted metabolomics and metagenomics were adopted for determining short-chain fatty acids (SCFAs) and bacteria that were specifically enriched by APS. Further in vitro experiment was carried out to test the capacity of SCFAs-producing of identified bacterium. Finally, the anti-NAFLD efficacy of identified bacterium was tested in HFD-fed mice.Our results first demonstrated the anti-NAFLD effect of APS in HFD-fed mice and the contribution of gut microbiota. Moreover, our results indicated that SCFAs, predominantly acetic acid were elevated in APS-supplemented mice and ex vivo experiment. Metagenomics revealed that D. vulgaris from Desulfovibrio genus was not only enriched by APS, but also a potent generator of acetic acid, which showed significant anti-NAFLD effects in HFD-fed mice. In addition, D. vulgaris modulated the hepatic gene expression pattern of lipids metabolism, particularly suppressed hepatic fatty acid synthase (FASN) and CD36 protein expression.Our results demonstrate that APS enriched D. vulgaris is effective on attenuating hepatic steatosis possibly through producing acetic acid, and modulation on hepatic lipids metabolism in mice. Further studies are warranted to explore the long-term impacts of D. vulgaris on host metabolism and the underlying mechanism.
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Affiliation(s)
- Ying Hong
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China,CONTACT Ningning Zheng Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Sheng
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Zhong
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, China
| | - Xin Tao
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weize Zhu
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Junli Ma
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Juan Yan
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Aihua Zhao
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xiaojiao Zheng
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Gaosong Wu
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bingbing Li
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bangxing Han
- Department of Biological and Pharmaceutical Engineering; Anhui Engineering Laboratory for Conservation and Sustainable Utilization of Traditional Chinese Medicine Resources, West Anhui University, Liu’an, China
| | - Kan Ding
- Glycochemistry and Glycobiology Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ningning Zheng
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Jia
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China,School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China,Wei Jia School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Houkai Li
- Functional Metabolomic and Gut Microbiome Laboratory, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Houkai Li Functional Metabolomic and Gut Microbiome Laboratory, Institute for Interdisciplinary Medicine Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai201203, China
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31
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Dendritic Cells and T Cell Subsets in the Development of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. ACTA MEDICA BULGARICA 2021. [DOI: 10.2478/amb-2021-0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are associated with steatosis, inflammation and fibrosis. Liver dendritic cells (DCs) are usually tolerogenic in the sinusoidal milleu composed of immunosuppressive cytokines. In NAFLD and NASH, DCs become pro-inflammatory and modulate hepatic immune response. Murine liver DCs are three major subtypes: classical (lymphoid) cDC1 or the crosspresenters (CD8α+CD103+), classical (myeloid) cDC2 (CD11b+) and plasmacytoid pDCs (PDCA-1+Siglec-H+) and two additional subtypes or lymphoid + myeloid DCs and NKDCs. Similarly, human liver DCs are three subtypes or CD141+CLEC9A+, CD1c+ (BDCA1+) and pDCs (CD303+BDCA2+). Compared to blood human hepatic DCs are less immature and predominantly induce regulatory T cells (Tregs) and IL-4 secreting T cells (Th2). DCs polarize T cells into different Th types that are in interrelations in NAFLD/NASH. T helper 1 (Th1) (T-bet) cells are associated with adipose tissue inflammation. The differentiation of Th2 (GATA3) cells is induced by IL-4 DCs, increased in NAFLD. Similarly, Th17 cells (RORγt/ RORc) are increased in NAFLD and NASH. Tregs (FoxP3) are increased in the liver in steatosis and Th22 cells (AHR) are elevated in diabetes mellitus 2 (DM2) and adiposity. CD8+ T cells γδT cells and MAIT cells also contribute to liver inflammation.
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Biagioli M, Fiorucci S. Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease. LIVER RESEARCH 2021; 5:119-141. [PMID: 39957845 PMCID: PMC11791866 DOI: 10.1016/j.livres.2021.08.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 07/29/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors. The two best characterized receptors of this family are the nuclear receptor, farnesoid X receptor (FXR) and the G protein-coupled receptor, G protein-coupled bile acid receptor 1 (GPBAR1). FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism, energy balance, autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders. Clinical trials in non-alcoholic fatty liver disease (NAFLD), however, have shown that selective FXR agonists cause side effects while their efficacy is partial. Because FXR and GPBAR1 exert additive effects, dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials. Here, we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Mayorga C, Palomares F, Cañas JA, Pérez-Sánchez N, Núñez R, Torres MJ, Gómez F. New Insights in Therapy for Food Allergy. Foods 2021; 10:foods10051037. [PMID: 34068667 PMCID: PMC8151532 DOI: 10.3390/foods10051037] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/24/2021] [Accepted: 05/05/2021] [Indexed: 12/23/2022] Open
Abstract
Food allergy is an increasing problem worldwide, with strict avoidance being classically the only available reliable treatment. The main objective of this review is to cover the latest information about the tools available for the diagnosis and treatment of food allergies. In recent years, many efforts have been made to better understand the humoral and cellular mechanisms involved in food allergy and to improve the strategies for diagnosis and treatment. This review illustrates IgE-mediated food hypersensitivity and provides a current description of the diagnostic strategies and advances in different treatments. Specific immunotherapy, including different routes of administration and new therapeutic approaches, such as hypoallergens and nanoparticles, are discussed in detail. Other treatments, such as biologics and microbiota, are also described. Therefore, we conclude that although important efforts have been made in improving therapies for food allergies, including innovative approaches mainly focusing on efficacy and safety, there is an urgent need to develop a set of basic and clinical results to help in the diagnosis and treatment of food allergies.
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Affiliation(s)
- Cristobalina Mayorga
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), 29009 Málaga, Spain; (F.P.); (J.A.C.); (R.N.)
- Allergy Clinical Unit, Hospital Regional Universitario de Málaga, 29071 Málaga, Spain; (N.P.-S.); (M.J.T.); (F.G.)
- Correspondence: ; Tel.: +34-951-290-224
| | - Francisca Palomares
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), 29009 Málaga, Spain; (F.P.); (J.A.C.); (R.N.)
| | - José A. Cañas
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), 29009 Málaga, Spain; (F.P.); (J.A.C.); (R.N.)
| | - Natalia Pérez-Sánchez
- Allergy Clinical Unit, Hospital Regional Universitario de Málaga, 29071 Málaga, Spain; (N.P.-S.); (M.J.T.); (F.G.)
| | - Rafael Núñez
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), 29009 Málaga, Spain; (F.P.); (J.A.C.); (R.N.)
| | - María José Torres
- Allergy Clinical Unit, Hospital Regional Universitario de Málaga, 29071 Málaga, Spain; (N.P.-S.); (M.J.T.); (F.G.)
- Medicine Department, Universidad de Málaga-UMA, 29071 Málaga, Spain
| | - Francisca Gómez
- Allergy Clinical Unit, Hospital Regional Universitario de Málaga, 29071 Málaga, Spain; (N.P.-S.); (M.J.T.); (F.G.)
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Méndez-Sánchez N, Córdova-Gallardo J, Barranco-Fragoso B, Eslam M. Hepatic Dendritic Cells in the Development and Progression of Metabolic Steatohepatitis. Front Immunol 2021; 12:641240. [PMID: 33833761 PMCID: PMC8021782 DOI: 10.3389/fimmu.2021.641240] [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: 12/13/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Metabolic Associated Fatty liver disease (MAFLD) is a global health problem and represents the most common cause of chronic liver disease in the world. MAFLD spectrum goes from simple steatosis to cirrhosis, in between metabolic steatohepatitis with progressive fibrosis, which pathogenesis is not completely understood. Hence, the role of the immune system has become an important fact in the trigger of inflammatory cascades in metabolic steatohepatitis and in the activation of hepatic stellate cells (HSCs). Among, the more studied immune cells in the pathogenesis of MAFLD are macrophages, T cells, natural killer and dendritic cells. In particular, hepatic dendritic cells had recently attracted a special attention, with a dual role in the pathogenesis of MAFLD. These cells have the capacity to switch from a tolerant state to active state inducing an inflammatory cascade. Furthermore, these cells play a role in the lipid storage within the liver, having, thus providing a crucial nexus between inflammation and lipid metabolism. In this review, we will discuss the current knowledge on the dual role of dendritic cells in lipid accumulation, as wells as in the triggering of hepatic inflammation and hepatocytes cell death in metabolic steatohepatitis.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Jacqueline Córdova-Gallardo
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Department of Hepatology, Service of Surgery and Obesity Clinic, General Hospital “Dr. Manuel Gea González”, Mexico City, Mexico
| | | | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
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Cicuéndez B, Ruiz-Garrido I, Mora A, Sabio G. Stress kinases in the development of liver steatosis and hepatocellular carcinoma. Mol Metab 2021; 50:101190. [PMID: 33588102 PMCID: PMC8324677 DOI: 10.1016/j.molmet.2021.101190] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/31/2020] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an important component of metabolic syndrome and one of the most prevalent liver diseases worldwide. This disorder is closely linked to hepatic insulin resistance, lipotoxicity, and inflammation. Although the mechanisms that cause steatosis and chronic liver injury in NAFLD remain unclear, a key component of this process is the activation of stress-activated kinases (SAPKs), including p38 and JNK in the liver and immune system. This review summarizes findings which indicate that the dysregulation of stress kinases plays a fundamental role in the development of steatosis and are important players in inducing liver fibrosis. To avoid the development of steatohepatitis and liver cancer, SAPK activity must be tightly regulated not only in the hepatocytes but also in other tissues, including cells of the immune system. Possible cellular mechanisms of SAPK actions are discussed.
Hepatic JNK triggers steatosis and insulin resistance, decreasing lipid oxidation and ketogenesis in HFD-fed mice. Decreased liver expression of p38α/β in HFD increases lipogenesis. Hepatic p38γ/δ drive insulin resistance and inhibit autophagy, which may lead to steatosis. Macrophage p38α/β promote cytokine production and M1 polarization, leading to lipid accumulation in hepatocytes. Myeloid p38γ/δ contribute to cytokine production and neutrophil migration, protecting against steatosis, diabetes and NAFLD. JNK1 and p38γ induce HCC while p38α blocks it. However, deletion of hepatic JNK1/2 induces cholangiocarcinoma. SAPK are potential therapeutic target for metabolic disorders, steatohepatitis and liver cancer.
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Affiliation(s)
- Beatriz Cicuéndez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Irene Ruiz-Garrido
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
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Peiseler M, Tacke F. Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:730. [PMID: 33578800 PMCID: PMC7916589 DOI: 10.3390/cancers13040730] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/07/2021] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.
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Affiliation(s)
- Moritz Peiseler
- Department of Hepatology & Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany;
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
- Department of Pharmacology & Physiology, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany;
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CX3CR1 Depletion Promotes the Formation of Platelet-Neutrophil Complexes and Aggravates Acute Peritonitis. Shock 2021; 56:287-297. [PMID: 33481549 DOI: 10.1097/shk.0000000000001733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Peritonitis is a life-threatening condition on intensive care units. Inflammatory cytokines and their receptors drive inflammation, cause the formation of platelet-neutrophil complexes (PNCs) and therefore the migration of polymorphonuclear neutrophils (PMNs) into the inflamed tissue. CX3CL1 and its receptor CX3CR1 are expressed in various cells, and promote inflammation. The shedding of CX3CL1 is mediated by a disintegrin and metalloprotease (ADAM) 17. The role of the CX3CL1-CX3CR1 axis in acute peritonitis remains elusive. METHODS In zymosan-induced peritonitis, we determined the formation of PNCs in the blood and the expression of PNC-related molecules on PNCs. PMN migration into the peritoneal lavage was evaluated in wild-type (WT) and CX3CR1-/- animals by flow cytometry. CX3CL1, ADAM17, and the expression of various inflammatory cytokines were detected. Further, we determined the inflammation-associated activation of the intracellular transcription factor extracellular signal-regulated kinase 1/2 (ERK1/2) by Western blot. RESULTS The PMN accumulation in the peritoneal lavage and the PNC formation in the circulation were significantly raised in CX3CR1-/- compared with WT animals. The expression of PNC-related selectins on PNCs was significantly increased in the blood of CX3CR1-/- animals, as well as cytokine levels. Further, we observed an increased activation of ERK1/2 and elevated ADAM17 expression in CX3CR1-/- during acute inflammation. Selective ERK1/2 inhibition ameliorated inflammation-related increased ADAM17 expression. CONCLUSIONS A CX3CR1 deficiency raised the release of inflammatory cytokines and increased the PNC formation respectively PMN migration via an elevated ERK1/2 activation during acute peritonitis. Further, we observed a link between the ERK1/2 activation and an elevated ADAM17 expression on PNC-related platelets and PMNs during inflammation. Our data thus illustrate a crucial role of CX3CR1 on the formation of PNCs and regulating inflammation in acute peritonitis.
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Liu Z, Liu M, Fan M, Pan S, Li S, Chen M, Wang H. Metabolomic-proteomic combination analysis reveals the targets and molecular pathways associated with hydrogen sulfide alleviating NAFLD. Life Sci 2020; 264:118629. [PMID: 33131747 DOI: 10.1016/j.lfs.2020.118629] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/10/2020] [Accepted: 10/17/2020] [Indexed: 01/03/2023]
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. Exogenous H2S has been shown to effectively mitigate NAFLD, although little is known about the underlying targets and molecular mechanisms. METHODS C57BL/6 mice were fed with normal fat diet (NFD) or high fat diet (HFD) for a total 16 weeks, and HFD-fed mice were treated with saline or NaHS beginning in 12th week. The combination analysis of metabolomics and proteomics of liver tissues was firstly performed to discover the candidate targets and potential molecular pathways involved in H2S mitigating the NAFLD. KEY FINDINGS Compared with NaCl, H2S relieved NAFLD by reducing liver weight, body weight and lipid accumulation in liver, and improving liver pathology and serum biochemical parameters. There were 40 overlapping metabolites in the intersection analysis between comparative analysis of HFD + NaCl vs NFD and HFD + NaHS vs HFD + NaCl based on liver metabolomics. Moreover, a total of 58 proteins were obtained whose changes were reversed after treatment with H2S. A combined analysis of liver metabolomics and proteomics was then conducted, revealing 8 shared molecular pathways, as well as the enrichment of unsaturated fatty acids. In addition, Plin2 may also be a potential target of H2S via the regulation of lipid droplet degradation in alleviating NAFLD. SIGNIFICANCE We performed the first study combining metabolomics and proteomics to explore the mechanisms behind the alleviation of NAFLD by H2S. Our results not only provide evidence that H2S alleviates NAFLD but also reveals its possible molecular mechanisms and targets.
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Affiliation(s)
- Zhangnan Liu
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Meichen Liu
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Ming Fan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Sijing Pan
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Shaowei Li
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China
| | - Mingliang Chen
- School of Basic Medicine, Henan University, Kaifeng 475004, China.
| | - Huijuan Wang
- Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cellular and Molecular Immunology of Henan Province, Institute of Translational Medicine, School of Basic Medicine, Henan University, Kaifeng 475004, China.
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Lurje I, Hammerich L, Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J Mol Sci 2020; 21:ijms21197378. [PMID: 33036244 PMCID: PMC7583774 DOI: 10.3390/ijms21197378] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation.
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The role of neutrophils in innate immunity-driven nonalcoholic steatohepatitis: lessons learned and future promise. Hepatol Int 2020; 14:652-666. [PMID: 32880077 DOI: 10.1007/s12072-020-10081-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023]
Abstract
The enrichment of innate immune cells and the enhanced inflammation represent the hallmark of non-alcoholic steatohepatitis (NASH), the advanced subtype with a significantly increased risk of progression to end-stage liver diseases within the spectrum of non-alcoholic fatty liver disease. Neutrophils are traditionally recognized as key components in the innate immune system to defend against pathogens. Recently, a growing body of evidence supports neutrophils as emerging key player in mediating the transition from steatosis to NASH, which is largely inspired by the histological findings in human liver biopsy indicating the enhanced infiltration of neutrophils as one of the key histological features of NASH. In this review, we discuss data regarding histological perspectives of hepatic infiltration of neutrophils in NASH. We also highlight the pathophysiological role of neutrophils in promoting metabolic inflammation in the liver through the release of a vast array of granule proteins, the interaction with other pro-inflammatory immune cells, and the formation of neutrophil extracellular traps. Neutrophil granule proteins possess pleiotropic effects on regulating neutrophil biology and functions. A variety of granule proteins (including lipocalin-2, myeloperoxidase, proteinase 3, neutrophil elastase, etc.) produced by neutrophils enhance liver metabolic inflammation, thereby promoting NASH progression by mediating neutrophil-macrophage interaction. Therapeutically, pharmacological inhibitors targeting neutrophil granule proteins hold promise to combat NASH. In addition, this article also summarizes potentials of neutrophils and its derived various granule proteins for the accurate, even non-invasive diagnosis of NASH.
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Dilek N, Papapetropoulos A, Toliver-Kinsky T, Szabo C. Hydrogen sulfide: An endogenous regulator of the immune system. Pharmacol Res 2020; 161:105119. [PMID: 32781284 DOI: 10.1016/j.phrs.2020.105119] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022]
Abstract
Hydrogen sulfide (H2S) is now recognized as an endogenous signaling gasotransmitter in mammals. It is produced by mammalian cells and tissues by various enzymes - predominantly cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) - but part of the H2S is produced by the intestinal microbiota (colonic H2S-producing bacteria). Here we summarize the available information on the production and functional role of H2S in the various cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils) and adaptive immunity (T and B lymphocytes) under normal conditions and as it relates to the development of various inflammatory and immune diseases. Special attention is paid to the physiological and the pathophysiological aspects of the oral cavity and the colon, where the immune cells and the parenchymal cells are exposed to a special "H2S environment" due to bacterial H2S production. H2S has many cellular and molecular targets. Immune cells are "surrounded" by a "cloud" of H2S, as a result of endogenous H2S production and exogenous production from the surrounding parenchymal cells, which, in turn, importantly regulates their viability and function. Downregulation of endogenous H2S producing enzymes in various diseases, or genetic defects in H2S biosynthetic enzyme systems either lead to the development of spontaneous autoimmune disease or accelerate the onset and worsen the severity of various immune-mediated diseases (e.g. autoimmune rheumatoid arthritis or asthma). Low, regulated amounts of H2S, when therapeutically delivered by small molecule donors, improve the function of various immune cells, and protect them against dysfunction induced by various noxious stimuli (e.g. reactive oxygen species or oxidized LDL). These effects of H2S contribute to the maintenance of immune functions, can stimulate antimicrobial defenses and can exert anti-inflammatory therapeutic effects in various diseases.
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Affiliation(s)
- Nahzli Dilek
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece
| | - Tracy Toliver-Kinsky
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland; Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
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Sun HJ, Wu ZY, Nie XW, Wang XY, Bian JS. Implications of hydrogen sulfide in liver pathophysiology: Mechanistic insights and therapeutic potential. J Adv Res 2020; 27:127-135. [PMID: 33318872 PMCID: PMC7728580 DOI: 10.1016/j.jare.2020.05.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background Over the last several decades, hydrogen sulfide (H2S) has been found to exert multiple physiological functions in mammal systems. The endogenous production of H2S is primarily mediated by cystathione β-synthase (CBS), cystathione γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are widely expressed in the liver tissues and regulate hepatic functions by acting on various molecular targets. Aim of Review In the present review, we will highlight the recent advancements in the cellular events triggered by H2S under liver diseases. The therapeutic effects of H2S donors on hepatic diseases will also be discussed. Key Scientific Concepts of Review As a critical regulator of liver functions, H2S is critically involved in the etiology of various liver disorders, such as nonalcoholic steatohepatitis (NASH), hepatic fibrosis, hepatic ischemia/reperfusion (IR) injury, and liver cancer. Targeting H2S-producing enzymes may be a promising strategy for managing hepatic disorders.
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Key Words
- 3-MP, 3-mercaptopyruvate
- 3-MST, 3-mercaptopyruvate sulfurtransferase
- AGTR1, angiotensin II type 1 receptor
- AMPK, AMP-activated protein kinase
- Akt, protein kinase B
- CAT, cysteine aminotransferase
- CBS, cystathione β-synthase
- CO, carbon monoxide
- COX-2, cyclooxygenase-2
- CSE, cystathione γ-lyase
- CX3CR1, chemokine CX3C motif receptor 1
- Cancer
- DAO, D-amino acid oxidase
- DATS, Diallyl trisulfide
- EGFR, epidermal growth factor receptor
- ERK, extracellular regulated protein kinases
- FAS, fatty acid synthase
- Fibrosis
- H2S, hydrogen sulfide
- HFD, high fat diet
- HO-1, heme oxygenase 1
- Hydrogen sulfide
- IR, ischemia/reperfusion
- Liver disease
- MMP-2, matrix metalloproteinase 2
- NADH, nicotinamide adenine dinucleotide
- NADPH, nicotinamide adenine dinucleotide phosphate
- NAFLD, non-alcoholic fatty liver diseases
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-kappa B
- NaHS, sodium hydrosulfide
- Nrf2, nuclear factor erythroid2-related factor 2
- PI3K, phosphatidylinositol 3-kinase
- PLP, pyridoxal 5′-phosphate
- PPG, propargylglycine
- PTEN, phosphatase and tensin homolog deleted on chromosome ten
- SAC, S-allyl-cysteine
- SPRC, S-propargyl-cysteine
- STAT3, signal transducer and activator of transcription 3
- Steatosis
- VLDL, very low density lipoprotein
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Hai-Jian Sun
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Zhi-Yuan Wu
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xiao-Wei Nie
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Xin-Yu Wang
- Department of Endocrinology, The First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518037, China
| | - Jin-Song Bian
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.,National University of Singapore Research Institute, Suzhou 215000, China
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Ali A, Zhang Y, Fu M, Pei Y, Wu L, Wang R, Yang G. Cystathionine gamma-lyase/H 2S system suppresses hepatic acetyl-CoA accumulation and nonalcoholic fatty liver disease in mice. Life Sci 2020; 252:117661. [PMID: 32305523 DOI: 10.1016/j.lfs.2020.117661] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/05/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023]
Abstract
AIMS Hydrogen sulfide (H2S) as a novel gasotransmitter can be endogenously produced in liver by cystathionine gamma-lyase (CSE). The dysfunctions of CSE/H2S system have been linked to various liver diseases. Acetyl-CoA is the key intermediate from the metabolism of lipid. This study examined the roles of H2S in hepatic acetyl-CoA and lipid metabolism. MATERIALS AND METHODS Both in vitro cell model and in vivo animal model of lipid accumulation were used in this study. Western blotting and real-time PCR were used for analysis of protein and mRNA expression. Acetyl-CoA was analyzed by a coupled enzyme assay, and lipid accumulation was observed with Oil Red O staining. KEY FINDINGS Incubation of human liver carcinoma (HepG2) cells with a mixture of free fatty acids (FFAs) or high glucose reduced CSE expression and H2S production, promoted intracellular accumulation of acetyl-CoA and lipid. Supply of exogenous NaHS or cysteine reduced acetyl-CoA contents and lipid accumulation, while blockage of CSE activity promoted intracellular lipid accumulation. Furthermore, H2S blocked FFAs-induced transcriptions of de novo lipogenesis, inflammation, and fibrosis-related genes. In vivo, knockout of CSE gene stimulated more hepatic acetyl-CoA and lipid accumulation in mice induced by high-fat choline-deficient diet. The expressions of lipogenesis, inflammation, and fibrosis-related genes were significantly higher in liver tissues from CSE knockout mice when compared with wild-type mice. SIGNIFICANCE CSE/H2S system is indispensable for maintaining the homeostasis of acetyl-CoA and lipid accumulation and protecting from the development of inflammation and fibrosis in liver under excessive caloric ingestion.
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Affiliation(s)
- Amr Ali
- Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Yanjie Zhang
- Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Life Science, Shanxi University, Taiyuan, China
| | - Ming Fu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Human Kinetics, Laurentian University, Sudbury, Canada; Health Science North Research Institute, Sudbury, Canada
| | - Yanxi Pei
- School of Life Science, Shanxi University, Taiyuan, China
| | - Lingyun Wu
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; School of Human Kinetics, Laurentian University, Sudbury, Canada; Health Science North Research Institute, Sudbury, Canada
| | - Rui Wang
- Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada
| | - Guangdong Yang
- Department of Chemistry and Biochemistry, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
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Méndez-Sánchez N, Valencia-Rodríguez A, Coronel-Castillo C, Vera-Barajas A, Contreras-Carmona J, Ponciano-Rodríguez G, Zamora-Valdés D. The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:400. [PMID: 32355844 PMCID: PMC7186641 DOI: 10.21037/atm.2020.02.184] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 02/29/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is considered the advanced stage of non-alcoholic fatty liver disease (NAFLD). It is characterized by liver steatosis, inflammation and different degrees of fibrosis. Although the exact mechanisms by which fatty liver progresses to NASH are still not well understood, innate and adaptive immune responses seem to be essential key regulators in the establishment, progression, and chronicity of these disease. Diet-induced lipid overload of parenchymal and non-parenchymal liver cells is considered the first step for the development of fatty liver with the consequent organelle dysfunction, cellular stress and liver injury. These will generate the production of pro-inflammatory cytokines, chemokines and damage-associated molecular patterns (DAMPs) that will upregulate the activation of Kupffer cells (KCs) and monocyte-derived macrophages (MMs) favoring the polarization of the tolerogenic environment of the liver to an immunogenic phenotype with the resulting transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts developing fibrosis. In the long run, dendritic cells (DCs) will activate CD4+ T cells polarizing into the pro-inflammatory lymphocytes Th1 and Th17 worsening the liver damage and inflammation. Therefore, the objective of this review is to discuss in a systematic way the mechanisms known so far of the immune and non-proper immune liver cells in the development and progression of NASH.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
- Faculty of Medicine. National Autonomous University of Mexico, Mexico City, Mexico
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Feng D. The alteration of immune cells in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. LIVER RESEARCH 2020. [DOI: 10.1016/j.livres.2020.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Abstract
In the past decade, nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease and cirrhosis, as well as an important risk factor for hepatocellular carcinoma (HCC). NAFLD encompasses a spectrum of liver lesions, including simple steatosis, steatohepatitis and fibrosis. Although steatosis is often harmless, the lobular inflammation that characterizes nonalcoholic steatohepatitis (NASH) is considered a driving force in the progression of NAFLD. The current view is that innate immune mechanisms represent a key element in supporting hepatic inflammation in NASH. However, increasing evidence points to the role of adaptive immunity as an additional factor promoting liver inflammation. This Review discusses data regarding the role of B cells and T cells in sustaining the progression of NASH to fibrosis and HCC, along with the findings that antigens originating from oxidative stress act as a trigger for immune responses. We also highlight the mechanisms affecting liver immune tolerance in the setting of steatohepatitis that favour lymphocyte activation. Finally, we analyse emerging evidence concerning the possible application of immune modulating treatments in NASH therapy.
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Affiliation(s)
- Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of East Piedmont, Novara, Italy
| | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University of East Piedmont, Novara, Italy.
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Stratton JA, Holmes A, Rosin NL, Sinha S, Vohra M, Burma NE, Trang T, Midha R, Biernaskie J. Macrophages Regulate Schwann Cell Maturation after Nerve Injury. Cell Rep 2019; 24:2561-2572.e6. [PMID: 30184491 DOI: 10.1016/j.celrep.2018.08.004] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/15/2018] [Accepted: 07/29/2018] [Indexed: 12/26/2022] Open
Abstract
Pro-regenerative macrophages are well known for their role in promoting tissue repair; however, their specific roles in promoting regeneration of the injured nerve are not well defined. Specifically, how macrophages interact with Schwann cells following injury during remyelination has been largely unexplored. We demonstrate that after injury, including in humans, macrophages function to clear debris and persist within the nerve microenvironment. Macrophage ablation immediately preceding remyelination results in an increase in immature Schwann cell density, a reduction in remyelination, and long-term deficits in conduction velocity. Targeted RNA-seq of macrophages from injured nerve identified Gas6 as one of several candidate factors involved in regulating Schwann cell dynamics. Functional studies show that the absence of Gas6 within monocyte lineage cells impairs Schwann cell remyelination within the injured nerve. These results demonstrate a role for macrophages in regulating Schwann cell function during nerve regeneration and highlight a molecular mechanism by which this occurs.
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Affiliation(s)
- Jo Anne Stratton
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Alexandra Holmes
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Nicole L Rosin
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Sarthak Sinha
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Mohit Vohra
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Nicole E Burma
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Tuan Trang
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Rajiv Midha
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
| | - Jeff Biernaskie
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
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Sutti S, Bruzzì S, Heymann F, Liepelt A, Krenkel O, Toscani A, Ramavath NN, Cotella D, Albano E, Tacke F. CX 3CR1 Mediates the Development of Monocyte-Derived Dendritic Cells during Hepatic Inflammation. Cells 2019; 8:1099. [PMID: 31540356 PMCID: PMC6770190 DOI: 10.3390/cells8091099] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/05/2019] [Accepted: 09/14/2019] [Indexed: 12/12/2022] Open
Abstract
Recent evidence suggests that hepatic dendritic cells (HDCs) contribute to the evolution of chronic liver diseases. However, the HDC subsets involved and the mechanisms driving these responses are still poorly understood. In this study, we have investigated the role of the fractalkine receptor CX3CR1 in modulating monocyte-derived dendritic cell (moDC) differentiation during liver inflammation. The phenotype of HDC and functional relevance of CX3CR1 was assessed in mice following necro-inflammatory liver injury induced by the hepatotoxic agent carbon tetrachloride (CCl4) and in steatohepatitis caused by a methionine/choline-deficient (MCD) diet. In both the experimental models, hepatic inflammation was associated with a massive expansion of CD11c+/MHCIIhigh/CD11b+ myeloid HDCs. These cells also expressed the monocyte markers Ly6C, chemokine (C-C Motif) receptor 2 (CCR2), F4/80 and CD88, along with CX3CR1, allowing their tentative identification as moDCs. Mice defective in CX3CR1 showed a reduction in liver-moDC recruitment following CCl4 poisoning in parallel with a defective maturation of monocytes into moDCs. The lack of CX3CR1 also affected moDC differentiation from bone marrow myeloid cells induced by granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) in vitro. In wild-type mice, treatment with the CX3CR1 antagonist CX3-AT (150 µg, i.p.) 24 h after CCl4 administration reduced liver moDCS and significantly ameliorated hepatic injury and inflammation. Altogether, these results highlight the possible involvement of moDCs in promoting hepatic inflammation following liver injury and indicated a novel role of CX3CL1/CX3CR1 dyad in driving the differentiation of hepatic moDCs.
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Affiliation(s)
- Salvatore Sutti
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Stefania Bruzzì
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Felix Heymann
- Department of Hepatology and Gastroenterology, Charité University Medical Center Berlin, 10117 Berlin, Germany.
| | - Anke Liepelt
- Department of Medicine III, RWTH-University Hospital Aachen, 52074 Aachen, Germany.
| | - Oliver Krenkel
- Department of Medicine III, RWTH-University Hospital Aachen, 52074 Aachen, Germany.
| | - Alberto Toscani
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Naresh Naik Ramavath
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Diego Cotella
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Emanuele Albano
- Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medical Center Berlin, 10117 Berlin, Germany.
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Das T, Bergen IM, Koudstaal T, van Hulst JA, van Loo G, Boonstra A, Vanwolleghem T, Leung PS, Gershwin ME, Hendriks RW, Kool M. DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology. J Autoimmun 2019; 102:167-178. [DOI: 10.1016/j.jaut.2019.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/27/2019] [Accepted: 05/05/2019] [Indexed: 02/06/2023]
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Jaiswal N, Agrawal S, Agrawal A. High fructose-induced metabolic changes enhance inflammation in human dendritic cells. Clin Exp Immunol 2019; 197:237-249. [PMID: 30919933 DOI: 10.1111/cei.13299] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2019] [Indexed: 12/25/2022] Open
Abstract
Dendritic cells (DCs) are critical antigen-presenting cells which are the initiators and regulators of the immune response. Numerous studies support the idea that dietary sugars influence DC functions. Increased consumption of fructose has been thought to be the leading cause of metabolic disorders. Although evidence supports their association with immune dysfunction, the specific mechanisms are not well understood. Fructose is one of the main dietary sugars in our diet. Therefore, here we compared the effect of fructose and glucose on the functions of human DCs. High levels of D-fructose compared to D-glucose led to activation of DCs in vitro by promoting interleukin (IL)-6 and IL-1β production. Moreover, fructose exposed DCs also induced interferon (IFN)-γ secretion from T cells. Proinflammatory response of DCs in high fructose environment was found to be independent of the major known metabolic regulators or glycolytic control. Instead, DC activation on acute exposure to fructose was via activation of receptor for advanced glycation end product (RAGE) in response to increased accumulation of advanced glycation end products (AGE). However, chronic exposure of DCs to high fructose environment induced a shift towards glycolysis compared to glucose cultured DCs. Further investigations revealed that the AGEs formed by fructose induced increased levels of inflammatory cytokines in DCs compared to AGEs from glucose. In summary, understanding the link between metabolic changes and fructose-induced DC activation compared to glucose has broad implications for immune dysfunction associated with metabolic disorders.
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Affiliation(s)
- N Jaiswal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - S Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
| | - A Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, USA
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