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Wang Z, Liang G, Peng J, Gu Y, Zhang X, Ding C, Yu T, Li Z. Sirtuin 7 Promotes Alcohol-Associated Liver Injury via Modulating Myeloid Cell Chemokine (C-C Motif) Ligand 2 Secretion through the NF-κB Signaling Pathway. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:575-588. [PMID: 39746506 DOI: 10.1016/j.ajpath.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/07/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025]
Abstract
The pathogenesis of alcohol-associated liver disease (ALD) involves ethanol-induced enhancement of gut permeability, bacterial products released from intestine and intrahepatic inflammation, and liver damage. Hepatic macrophages play a crucial role in mediating inflammatory response by alcohol. Sirtuin 7 (SIRT7), a NAD+-dependent type III histone deacetylase, is being recognized as a therapeutic target in various human diseases. Emerging evidence shows that SIRT7 participates in immune regulation, but whether it is involved in ALD remains elusive. In the present study, myeloid cell-specific Sirt7 knockout mice (Lyz2-Sirt7-/-) were used to show that knockout Sirt7 in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. Chemokine (C-C motif) ligand 2 (CCL2) was identified as the main target impaired by Sirt7 knockout after alcohol. In vitro studies confirmed that Sirt7 knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At the molecular level, knockout of Sirt7 significantly impaired lipopolysaccharide-induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol-induced liver injury and hepatic inflammation via preventing CCL2 in vivo. The current data thus uncovered a previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through the NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism-based therapeutic options for ALD.
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Affiliation(s)
- Zhiqiang Wang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China; Human Anatomy Teaching and Experimental Center, School of Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Gaoshuang Liang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Jinying Peng
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Yiying Gu
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Xiangwen Zhang
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Cong Ding
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Tingzi Yu
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China
| | - Zhuan Li
- The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, The Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Institute of Interdisciplinary Studies, Hunan Normal University School of Pharmaceutical Science, Changsha, China.
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Hou PF, Yao Y, Bai Q, Lang HD, Qin Y, Zhu JD, Zhang QY, Yi L, Mi MT. Short term high-fat diet induced liver ILC1 differentiation associated with the TLR9 activation. J Nutr Biochem 2025; 136:109810. [PMID: 39551166 DOI: 10.1016/j.jnutbio.2024.109810] [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: 05/21/2024] [Revised: 10/24/2024] [Accepted: 11/12/2024] [Indexed: 11/19/2024]
Abstract
The health impact of dietary fat is a significant nutritional concern. However, the effects of high-fat diet on immune system particularly the liver regional immune function remains still unclear. Liver ILC1 has been recently identified as playing crucial roles in anti-viral defense, liver regeneration, and protection against acute liver injury. Here, in a mouse model, we uncovered that short term high-fat diet for 2 weeks obviously increased the frequency and number of ILC1 in liver. The production of TNF-α and expressions of TRAIL, CXCR3 and CXCR6 were also increased. Furthermore, EASY-RNAseq and ATAC-seq of liver ILC1 clarified the transcriptome characteristics and chromatin accessibility in response to short term high-fat diet, which were involved with lymphocyte differentiation. Mechanistically, we demonstrated that accumulation of liver ILC1 induced by short term high-fat diet was dependent on a TLR9-mediated differentiation through TLR9 inhibitor. Taken together, these findings shed light on the effect and underlying mechanism of short term high-fat diet on liver ILC1 differentiation and provide nutritional strategies and theoretical basis for the liver regional immune function regulation.
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Affiliation(s)
- Peng-Fei Hou
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Yu Yao
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Qian Bai
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - He-Dong Lang
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Yu Qin
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Jun-Dong Zhu
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Qian-Yong Zhang
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China
| | - Long Yi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China.
| | - Man-Tian Mi
- Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Health, Chongqing Medical Nutrition Research Center, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, PR China.
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Brummer C, Singer K, Brand A, Bruss C, Renner K, Herr W, Pukrop T, Dorn C, Hellerbrand C, Matos C, Kreutz M. Sex-Dependent T Cell Dysregulation in Mice with Diet-Induced Obesity. Int J Mol Sci 2024; 25:8234. [PMID: 39125804 PMCID: PMC11311663 DOI: 10.3390/ijms25158234] [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: 06/16/2024] [Revised: 07/20/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.
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Affiliation(s)
- Christina Brummer
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
| | - Katrin Singer
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
| | - Almut Brand
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
| | - Christina Bruss
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
- Department of Gynecology and Obstetrics, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
| | - Kathrin Renner
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
- Department of Otorhinolaryngology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
| | - Tobias Pukrop
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
- Comprehensive Cancer Center Eastern Bavaria (CCCO), 93053 Regensburg, Germany
- Center of Translational Oncology (CTO), 93053 Regensburg, Germany
| | - Christoph Dorn
- Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, University of Erlangen, 91054 Erlangen, Germany
| | - Carina Matos
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
| | - Marina Kreutz
- Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053 Regensburg, Germany
- Bavarian Cancer Research Centre (BZKF), 93053 Regensburg, Germany
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Rao PL, Shen YH, Song YJ, Xu Y, Xu HX. Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117237. [PMID: 37769885 DOI: 10.1016/j.jep.2023.117237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/14/2023] [Accepted: 09/26/2023] [Indexed: 10/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Prunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the "Shen Nong's Classic of the Materia Medica". PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated. AIM OF THE STUDY This study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury. MATERIALS AND METHODS We used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD. RESULTS In ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway. CONCLUSION These findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases.
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Affiliation(s)
- Pei-Li Rao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yun-Hui Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China
| | - Yi-Jie Song
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China.
| | - Hong-Xi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China.
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Zhang C, Sui Y, Liu S, Yang M. The Roles of Myeloid-Derived Suppressor Cells in Liver Disease. Biomedicines 2024; 12:299. [PMID: 38397901 PMCID: PMC10886773 DOI: 10.3390/biomedicines12020299] [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: 11/30/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, USA;
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
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Zhao J, Zhang X, Li Y, Yu J, Chen Z, Niu Y, Ran S, Wang S, Ye W, Luo Z, Li X, Hao Y, Zong J, Xia C, Xia J, Wu J. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front Immunol 2023; 14:1314123. [PMID: 38155961 PMCID: PMC10754533 DOI: 10.3389/fimmu.2023.1314123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023] Open
Abstract
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
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Affiliation(s)
- Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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Sun J, Zhao P, Shi Y, Li Y. Recent insight into the role of macrophage in alcohol-associated liver disease: a mini-review. Front Cell Dev Biol 2023; 11:1292016. [PMID: 38094617 PMCID: PMC10716218 DOI: 10.3389/fcell.2023.1292016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/20/2023] [Indexed: 03/05/2025] Open
Abstract
Alcohol-associated liver disease (ALD) is a condition that develops due to prolonged and excessive alcohol consumption. It encompasses various stages of liver damage, including fatty liver, alcoholic hepatitis, and cirrhosis. Immune cells, particularly macrophages, of various types play a significant role in the onset and progression of the disease. Macrophages observed in the liver exhibit diverse differentiation forms, and perform a range of functions. Beyond M1 and M2 macrophages, human macrophages can polarize into distinct phenotypes in response to various stimuli. Recent advancements have improved our understanding of macrophage diversity and their role in the progression of ALD. This mini-review provides a concise overview of the latest findings on the role and differentiation of macrophages in ALD. Additionally, it discusses potential therapeutic targets associated with macrophages and explores potential therapeutic strategies.
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Affiliation(s)
- Jialiang Sun
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Peiliang Zhao
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Yanan Li
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, China
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Diaz LA, Winder GS, Leggio L, Bajaj JS, Bataller R, Arab JP. New insights into the molecular basis of alcohol abstinence and relapse in alcohol-associated liver disease. Hepatology 2023:01515467-990000000-00605. [PMID: 37862466 DOI: 10.1097/hep.0000000000000645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/11/2023] [Indexed: 10/22/2023]
Abstract
Alcohol use disorder remains a significant public health concern, affecting around 5% of adults worldwide. Novel pathways of damage have been described during the last years, providing insight into the mechanism of injury due to alcohol misuse beyond the direct effect of ethanol byproducts on the liver parenchyma and neurobehavioral mechanisms. Thus, the gut-liver-brain axis and immune system involvement could be therapeutic targets for alcohol use disorder. In particular, changes in gut microbiota composition and function, and bile acid homeostasis, have been shown with alcohol consumption and cessation. Alcohol can also directly disrupt intestinal and blood-brain barriers. Activation of the immune system can be triggered by intestinal barrier dysfunction and translocation of bacteria, pathogen-associated molecular patterns (such as lipopolysaccharide), cytokines, and damage-associated molecular patterns. These factors, in turn, promote liver and brain inflammation and the progression of liver fibrosis. Other involved mechanisms include oxidative stress, apoptosis, autophagy, and the release of extracellular vesicles and miRNA from hepatocytes. Potential therapeutic targets include gut microbiota (probiotics and fecal microbiota transplantation), neuroinflammatory pathways, as well as neuroendocrine pathways, for example, the ghrelin system (ghrelin receptor blockade), incretin mimetics (glucagon-like peptide-1 analogs), and the mineralocorticoid receptor system (spironolactone). In addition, support with psychological and behavioral treatments is essential to address the multiple dimensions of alcohol use disorder. In the future, a personalized approach considering these novel targets can contribute to significantly decreasing the alcohol-associated burden of disease.
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Affiliation(s)
- Luis Antonio Diaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institutes of Health, NIDA and NIAAA, Baltimore, Maryland, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Health Care System, Richmond, Virginia, USA
| | - Ramon Bataller
- Liver Unit, Hospital Clinic, Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University, London, Ontario, Canada
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Calabrese FM, Celano G, Bonfiglio C, Campanella A, Franco I, Annunziato A, Giannelli G, Osella AR, De Angelis M. Synergistic Effect of Diet and Physical Activity on a NAFLD Cohort: Metabolomics Profile and Clinical Variable Evaluation. Nutrients 2023; 15:nu15112457. [PMID: 37299420 DOI: 10.3390/nu15112457] [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: 04/19/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Together with its comorbidities, nonalcoholic fatty liver disease (NAFLD) is likely to rise further with the obesity epidemic. However, the literature's evidence shows how its progression can be reduced by the administration of calorie-restrictive dietary interventions and physical activity regimens. The liver function and the gut microbiota have been demonstrated to be closely related. With the aim of ascertaining the impact of a treatment based on the combination of diet and physical activity (versus physical activity alone), we recruited 46 NAFLD patients who were divided into two groups. As a result, we traced the connection between volatile organic compounds (VOCs) from fecal metabolomics and a set of statistically filtered clinical variables. Additionally, we identified the relative abundances of gut microbiota taxa obtained from 16S rRNA gene sequencing. Statistically significant correlations emerged between VOCs and clinical parameters, as well as between VOCs and gut microbiota taxa. In comparison with a physical activity regimen alone, we disclose how ethyl valerate and pentanoic acid butyl ester, methyl valerate, and 5-hepten-2-one, 6-methyl changed because of the positive synergistic effect exerted by the combination of the Mediterranean diet and physical activity regimens. Moreover, 5-hepten-2-one, 6-methyl positively correlated with Sanguinobacteroides, as well as the two genera Oscillospiraceae-UCG002 and Ruminococcaceae UCG010 genera.
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Affiliation(s)
| | - Giuseppe Celano
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Caterina Bonfiglio
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy
| | - Angelo Campanella
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy
| | - Isabella Franco
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy
| | - Alessandro Annunziato
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Gianluigi Giannelli
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy
| | - Alberto Ruben Osella
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, Italy
| | - Maria De Angelis
- Department of Soil, Plant and Food Science, University of Bari Aldo Moro, 70126 Bari, Italy
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Zhang P, Li H, Peng B, Zhang Y, Liu K, Cheng K, Ming Y. Single-cell RNA transcriptomics reveals differences in the immune status of alcoholic and hepatitis B virus-related liver cirrhosis. Front Endocrinol (Lausanne) 2023; 14:1132085. [PMID: 36817578 PMCID: PMC9932584 DOI: 10.3389/fendo.2023.1132085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Alcoholic and hepatitis B virus (HBV)-related liver cirrhosis has placed a tremendous burden on the healthcare system with limited treatment options. This study explored the differences in the immune status of alcoholic and HBV-related liver cirrhosis. METHODS A total of 15 human liver samples from the Third Xiangya Hospital of Central South University, including five healthy controls (HC group), five alcoholic cirrhosis patients (ALC group), and five HBV-related cirrhosis patients (HBV group) were used. Of these, eight samples, including 3 HC group, 2 ALC group and 3 HBV group, were randomly collected to do single-cell RNA sequencing (scRNA-seq). The degree of steatosis was assessed by H&E staining and the presence of intrahepatic immune cells was evaluated by immunochemistry (IHC). RESULTS The immune status of alcoholic and HBV-related liver cirrhosis differed significantly. ScRNA-seq analysis identified a higher ratio of intrahepatic monocyte/macrophages and an obvious decreased ratio of T cells and B cells in the ALC group than in the HBV group. IHC staining of intrahepatic monocyte/macrophages, T and B cell exhibited similar results with scRNA-seq analysis. CD5L+ Kupffer cells, a cell type involved in lipid metabolism, were the major monocyte/macrophage subset in ALC liver tissue. H&E staining indicated that the level of steatosis was more severe in the ALC than in the HBV group. Ligand/receptor analysis showed that the T cell exhaustion observed in the ALC liver may be related to the expression of Galectin-9 on Kupffer cells. Fewer B cells were also found in the ALC group and most had higher lipid metabolism, reduced ribosomal activity, and a dysregulated mitochondrial oxidative phosphorylation system. Moreover, scRNA-seq showed a significantly lower ratio of plasma B cells, indicating that the humoral immune response in the ALC liver was similarly dysfunctional. Ligand/receptor analysis also discovered that Galectin-9 expressed on Kupffer cells may inhibit humoral immunity. CONCLUSION Patients with ALC have different immune characteristics than those with HBV-induced cirrhosis, including an increased ratio of intrahepatic monocyte/macrophages and a dysfunctional adaptive immune response in the liver. Galectin-9 could serve as a potential therapeutic target for ALC treatment.
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Affiliation(s)
- Pengpeng Zhang
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Hao Li
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Bo Peng
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Yu Zhang
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Kai Liu
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Ke Cheng
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
| | - Yingzi Ming
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Engineering & Technology Research Center for Transplantation Medicine of National Ministry of Health, Changsha, Hunan, China
- *Correspondence: Yingzi Ming,
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Zheng S, Yang W, Yao D, Tang S, Hou J, Chang X. A comparative study on roles of natural killer T cells in two diet-induced non-alcoholic steatohepatitis-related fibrosis in mice. Ann Med 2022; 54:2233-2245. [PMID: 35950602 PMCID: PMC9377241 DOI: 10.1080/07853890.2022.2108894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Immune responses are important in the progression of non-alcoholic fatty liver disease (NAFLD). Natural killer T (NKT) cells are main components of the innate immune system that modulate immunity. However, the role of NKT cells in NAFLD remains controversial. OBJECTIVE We aimed to investigate the role of NKT cells in non-alcoholic steatohepatitis (NASH)-related fibrosis in fast food diet (FFD)- and methionine choline-deficient (MCD) diet-induced mouse models. METHODS Hepatic NKT cells were analysed in wild-type (WT) and CD1d-/- mice fed FFD or MCD diets. Hepatic pathology, cytokine profiles and liver fibrosis were evaluated. Furthermore, the effect of chronic administration of α-galactosylceramide (α-GalCer) on liver fibrosis was investigated in both FFD- and MCD-treated mice. RESULTS FFD induced a significant depletion of hepatic NKT cells, thus leading to mild to moderate NASH and early-stage fibrosis, while mice fed MCD diets developed severe liver inflammation and progressive fibrosis without a significant change in hepatic NKT cell abundance. FFD induced a similar liver fibrogenic response in CD1d-/- and WT mice, while MCD induced a higher hepatic mRNA expression of Col1α1 and TIMP1 as well as relative fibrosis density in CD1d-/- mice than WT mice (31.8 vs. 16.3, p = .039; 40.0 vs. 22.6, p = .019; 2.24 vs. 1.59, p = .036). Chronic administration of α-GalCer induced a higher hepatic mRNA expression of TIMP1 in MCD-treated mice than controls (36.7 vs. 14.9, p = .005). CONCLUSION NKT cells have protective roles in NAFLD as the disease progresses. During diet-induced steatosis, mild to moderate NASH and the early stage of fibrosis, hepatic NKT cells are relatively depleted, leading to a proinflammatory status. In severe NASH and the advanced stage of liver fibrosis, NKT cells play a role in inhibiting the NASH-related fibrogenic response. Chronic administration of α-GalCer induces NKT cell anergy and tolerance, which may play a role in promoting the liver fibrogenic response.
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Affiliation(s)
- Shumei Zheng
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Wenzhuo Yang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Shanghai Tongji University, Shanghai, China
| | - Dongmei Yao
- Department of Gastroenterology and Hepatology, the Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shanhong Tang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Juanni Hou
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
| | - Xing Chang
- Department of Gastroenterology and Hepatology, The General Hospital of Western Theater Command, Chengdu, China
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Frick K, Beller EA, Kalisvaart M, Dutkowski P, Schüpbach RA, Klinzing S. Procalcitonin in early allograft dysfunction after orthotopic liver transplantation: a retrospective single centre study. BMC Gastroenterol 2022; 22:404. [PMID: 36045337 PMCID: PMC9429388 DOI: 10.1186/s12876-022-02486-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/16/2022] [Indexed: 11/11/2022] Open
Abstract
Background Ischemia–reperfusion injury (IRI) is the pathophysiological hallmark of hepatic dysfunction after orthotopic liver transplantation (OLT). Related to IRI, early allograft dysfunction (EAD) after OLT affects short- and long-term outcome. During inflammatory states, the liver seems to be the main source of procalcitonin (PCT), which has been shown to increase independently of bacterial infection. This study investigates the association of PCT, IRI and EAD as well as the predictive value of PCT during the first postoperative week in terms of short- and long-term outcome after OLT. Methods Patients ≥ 18 years undergoing OLT between January 2016 and April 2020 at the University Hospital of Zurich were eligible for this retrospective study. Patients with incomplete PCT data on postoperative days (POD) 1 + 2 or combined liver-kidney transplantation were excluded. The PCT course during the first postoperative week, its association with EAD, defined by the criteria of Olthoff, and IRI, defined as aminotransferase level > 2000 IU/L within 2 PODs, were analysed. Finally, 90-day as well as 12-month graft and patient survival were assessed. Results Of 234 patients undergoing OLT, 110 patients were included. Overall, EAD and IRI patients had significantly higher median PCT values on POD 2 [31.3 (9.7–53.8) mcg/l vs. 11.1 (5.3–25.0) mcg/l; p < 0.001 and 27.7 (9.7–51.9) mcg/l vs. 11.5 (5.5–25.2) mcg/l; p < 0.001] and impaired 90-day graft survival (79.2% vs. 95.2%; p = 0.01 and 80.4% vs. 93.8%; p = 0.033). IRI patients with PCT < 15 mcg/l on POD 2 had reduced 90-day graft and patient survival (57.9% vs. 93.8%; p = 0.001 and 68.4% vs. 93.8%; p = 0.008) as well as impaired 12-month graft and patient survival (57.9% vs. 96.3%; p = 0.001 and 68.4% vs. 96.3%; p = 0.008), while the outcome of IRI patients with PCT > 15 mcg/l on POD 2 was comparable to that of patients without IRI/EAD. Conclusion Generally, PCT is increased in the early postoperative phase after OLT. Patients with EAD and IRI have a significantly increased PCT maximum on POD 2, and impaired 90-day graft survival. PCT measurement may have potential as an additional outcome predictor in the early phase after OLT, as in our subanalysis of IRI patients, PCT values < 15 mcg/l were associated with impaired outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02486-5.
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Tian J, Chung HK, Moon JS, Nga HT, Lee HY, Kim JT, Chang JY, Kang SG, Ryu D, Che X, Choi J, Tsukasaki M, Sasako T, Lee S, Shong M, Yi H. Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice. J Cachexia Sarcopenia Muscle 2022; 13:1785-1799. [PMID: 35306755 PMCID: PMC9178379 DOI: 10.1002/jcsm.12975] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 02/01/2022] [Accepted: 02/15/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass. METHODS MKO mice with lower muscle OxPhos were fed a normal chow or high-fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation. RESULTS MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response-related genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in grip strength and a higher drop rate in the wire hanging test (P < 0.01). Micro-computed tomography and von Kossa staining revealed that MKO mice developed a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic analysis of the BM revealed that mitochondrial stress responses in skeletal muscles induce an inflammatory response and adipogenesis in the BM and that the CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in MKO mice. In humans, patients with low body mass index (BMI = 17.2 ± 0.42 kg/m2 ) harboured a larger population of proinflammatory and cytotoxic senescent T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in the vastus lateralis, compared with controls with a normal BMI (23.7 ± 0.88 kg/m2 ) (P < 0.01). CONCLUSIONS Defects in muscle mitochondrial OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.
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Affiliation(s)
- Jingwen Tian
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Laboratory of Endocrinology and Immune SystemChungnam National University School of MedicineDaejeonKorea
| | - Hyo Kyun Chung
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Ji Sun Moon
- Laboratory of Endocrinology and Immune SystemChungnam National University School of MedicineDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Ha Thi Nga
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Laboratory of Endocrinology and Immune SystemChungnam National University School of MedicineDaejeonKorea
| | - Ho Yeop Lee
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Laboratory of Endocrinology and Immune SystemChungnam National University School of MedicineDaejeonKorea
| | - Jung Tae Kim
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Joon Young Chang
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Seul Gi Kang
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Dongryeol Ryu
- Department of Molecular Cell BiologySungkyunkwan University School of MedicineSuwonKorea
- Samsung Biomedical Research InstituteSamsung Medical CenterSeoulKorea
| | - Xiangguo Che
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, School of MedicineKyungpook National UniversityDaeguKorea
- Department of Internal Medicine, Rheumatology and ImmunologyThe Affiliated Hospital of Yanbian UniversityYanjiChina
| | - Je‐Yong Choi
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, BK21 Plus KNU Biomedical Convergence Program, School of MedicineKyungpook National UniversityDaeguKorea
| | - Masayuki Tsukasaki
- Department of Immunology, Graduate School of Medicine and Faculty of MedicineThe University of TokyoTokyoJapan
| | - Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Sang‐Hee Lee
- Bio‐Electron Microscopy Research Center (104‐Dong)Korea Basic Science InstituteCheongjuKorea
| | - Minho Shong
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
| | - Hyon‐Seung Yi
- Department of Medical ScienceChungnam National UniversityDaejeonKorea
- Laboratory of Endocrinology and Immune SystemChungnam National University School of MedicineDaejeonKorea
- Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonKorea
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Xu H, Wang H. Immune cells in alcohol-related liver disease. LIVER RESEARCH 2022; 6:1-9. [PMID: 39959807 PMCID: PMC11791833 DOI: 10.1016/j.livres.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/18/2021] [Accepted: 01/07/2022] [Indexed: 11/24/2022]
Abstract
Alcohol-related liver disease (ALD), which is caused by excessive alcohol consumption, is one of the most common types of liver disease and a primary cause of hepatic injury, with a disease spectrum that includes steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Various lines of evidence have indicated that immune cells play a significant role in the inflammatory processes of ALD. On the one hand, the liver contains various resident immune cells that have been proven to perform different functions in ALD. For example, in the progression of the disease, Kupffer cells (KCs) are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory cytokines. Moreover, alcohol intake has been shown to depress the function of natural killer cells. Additionally, two types of unconventional T cells (natural killer T cells and mucosal-associated invariant T cells) are involved in the development of ALD. On the other hand, alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells (neutrophils, T cells, macrophages, and mast cells) into the liver. The neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection processes. Additionally, alcohol intake can change the phenotype of T cells, resulting in their increased production of interleukin-17. Aside from KCs, infiltrating macrophages have also been observed in patients with ALD, but the roles of all of these cells in the progression of the disease have shown both similarities and differences. Additionally, the activated mast cells are also associated with the development of ALD. Herein, we review the diverse roles of the various immune cells in the progression of ALD.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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15
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Tian F, Jiang T, Qi X, Zhao Z, Li B, Aibibula M, Min H, Zhang J, Liu Y, Ma X. Role of Cytokines on the Progression of Liver Fibrosis in Mice Infected with Echinococcus multilocularis. Infect Drug Resist 2022; 14:5651-5660. [PMID: 34992391 PMCID: PMC8714463 DOI: 10.2147/idr.s344508] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/11/2021] [Indexed: 12/20/2022] Open
Abstract
Background Liver fibrosis is a significant pathological change of Echinococcus multilocularis (E. multilocularis) infection. This study aimed to explore the role of cytokines on the progression of liver fibrosis in mice infected with E. multilocularis. Methods Liver histopathological features at 2, 8, 30, 90 and 180 d were quantified by inflammatory severity score. The expression levels of inflammatory cytokines, fibrosis-related cytokines and hepatic cell apoptosis were measured using qRT-PCR and immunohistochemistry. Results At the early stage of infection, parasite stimulation triggers the rapid recruitment of immune cells, such as macrophages and neutrophils. These infiltrated immune cells then produce a large number of cytokines, such as iNOS (inducible nitric oxide synthase), a pro-inflammatory cytokine; TGF-β (transforming growth factor) activated HSCs (hepatic stellate cells) to promote the proliferation of fibroblasts and secretion of ECM (extracellular matrix); MMP9 (matrix metalloproteinase 9) degraded basal ECM and facilitated its replacement by a highly dense interstitial matrix. At the middle and late stages of infection, the expression of IL-10 (interleukin-10) with general inhibitory effect was increased. The imbalance of fiber formation and degradation aggravated liver fibrosis. Meanwhile, the whole process of E. multilocularis infection was accompanied by the necrosis and apoptosis of hepatic cells. Conclusion Along with the expansion of parasitic infection, dynamic changes in cytokine expression were observed on the liver fibrosis progression, which is helpful to provide some new ideas for the prevention and treatment of liver fibrosis in mice infected with E. multilocularis.
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Affiliation(s)
- Fengming Tian
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Tao Jiang
- Animal Experiment Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Xinwei Qi
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Zhenyu Zhao
- School of Stomatology, Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Bin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Madinaimu Aibibula
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Hongyue Min
- School of Basic Medicine, Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Jingyi Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Yumei Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
| | - Xiumin Ma
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China.,State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China.,School of Basic Medicine, Xinjiang Medical University, Urumqi, Xinjiang, 830011, People's Republic of China
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Wu JT, He BW, Cao JL, Yan JB, Chen ZY. Involvement of STING signaling pathway in non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2021; 29:1396-1401. [DOI: 10.11569/wcjd.v29.i24.1396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the major chronic liver diseases worldwide, which seriously threatens human health and has become a major public health problem. Immune mechanism plays a key role in the occurrence and development of NAFLD. Interferon gene stimulating factor (STING) is a key connector protein of the immune system, and its related signaling pathway has become a recent hot research topic. This signaling pathway may be involved in the occurrence and development of NAFLD by mediating liver inflammation, lipid metabolism, apoptosis, and other processes that affect liver metabolic homeostasis. Combining relevant reports and the latest literature, this paper reviews NAFLD and immunity, the composition of STING signaling pathway, and the relationship between the STING signaling pathway and NAFLD, in order to provide ideas for further in-depth study of the complex relationship between the STING signaling pathway and NAFLD and the development of relevant targeted drugs.
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Affiliation(s)
- Jin-Ting Wu
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Command, Hangzhou 310006, Zhejiang Province, China
| | - Bo-Wu He
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Command, Hangzhou 310006, Zhejiang Province, China
| | - Jie-Lu Cao
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Command, Hangzhou 310006, Zhejiang Province, China
| | - Jun-Bin Yan
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Command, Hangzhou 310006, Zhejiang Province, China
| | - Zhi-Yun Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou Command, Hangzhou 310006, Zhejiang Province, China
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Role of the Microenvironment in Mesenchymal Stem Cell-Based Strategies for Treating Human Liver Diseases. Stem Cells Int 2021; 2021:5513309. [PMID: 34824587 PMCID: PMC8610645 DOI: 10.1155/2021/5513309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/23/2021] [Accepted: 10/30/2021] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a severe health problem that endangers human health worldwide. Mesenchymal stem cell (MSC) therapy is a novel treatment for patients with different liver diseases due to its vast expansion potential and distinctive immunomodulatory properties. Despite several preclinical trials having confirmed the considerable efficacy of MSC therapy in liver diseases, the questionable safety and efficacy still limit its application. As a precursor cell, MSCs can adjust their characteristics in response to the surrounding microenvironment. The microenvironment provides physical and chemical factors essential for stem cell survival, proliferation, and differentiation. However, the mechanisms are still not completely understood. We, therefore, summarized the mechanisms underlying the MSC immune response, especially the interaction between MSCs and the liver microenvironment, discussing how to achieve better therapeutic effects.
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Lawal G, Xiao Y, Rahnemai-Azar AA, Tsilimigras DI, Kuang M, Bakopoulos A, Pawlik TM. The Immunology of Hepatocellular Carcinoma. Vaccines (Basel) 2021; 9:vaccines9101184. [PMID: 34696292 PMCID: PMC8538643 DOI: 10.3390/vaccines9101184] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/20/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.
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Affiliation(s)
- Gbemisola Lawal
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Yao Xiao
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Amir A. Rahnemai-Azar
- Division of Surgical Oncology, Department of Surgery, Arrowhead Regional Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA; (G.L.); (A.A.R.-A.)
| | - Diamantis I. Tsilimigras
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
- Correspondence: ; Tel.: +1-215-987-9177
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; (Y.X.); (M.K.)
| | - Anargyros Bakopoulos
- Department of Surgery, Attikon University Hospital, University of Athens, 12462 Athens, Greece;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA;
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Patel AM, Liu YS, Davies SP, Brown RM, Kelly DA, Scheel-Toellner D, Reynolds GM, Stamataki Z. The Role of B Cells in Adult and Paediatric Liver Injury. Front Immunol 2021; 12:729143. [PMID: 34630404 PMCID: PMC8495195 DOI: 10.3389/fimmu.2021.729143] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
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Affiliation(s)
- Arzoo M. Patel
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Yuxin S. Liu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Scott P. Davies
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rachel M. Brown
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Deirdre A. Kelly
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Dagmar Scheel-Toellner
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Gary M. Reynolds
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Ren X, Ju Y, Wang C, Wei R, Sun H, Zhang Q. MARCKS on Tumor-Associated Macrophages is Correlated with Immune Infiltrates and Poor Prognosis in Hepatocellular Carcinoma. Cancer Invest 2021; 39:756-768. [PMID: 34279157 DOI: 10.1080/07357907.2021.1950757] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is the fourth most common cause of cancer-related death. However, the cross-talk between tumor immune microenvironment and hepatocellular carcinoma (HCC) remains unclear. MATERIAL AND METHODS We analyzed the expression of miR-143-3p in exosomes from different HCC cell lines. Differentially expressed genes (DEGs) in Tumor-associated macrophages (TAMs) co-cultured with HCC cell lines were overlapped with miR-143-3p target genes. We used the Oncomine, Kaplan-Meier plotter, and The Cancer Genome Atlas (TCGA) databases to assess Myristoylated alanine-rich C-kinase substrate (MARCKS) expression in various types of cancers. The relationship between patient clinicopathological characteristics and MARCKS expression level was identified using the Kaplan-Meier plotter database. Last, we analyzed how MARCKS expression correlated with immune infiltration makers using the TCGA database, Tumor IMmune Estimation Resource (TIMER), and Gene Expression Profiling Interactive Analysis (GEPIA). RESULTS Exosomal miR-143-3p was elevated after IL-6 treatment in the HCC cell line. MARCKS, a target gene of miR-143-3p, was up-regulated in Tumor-associated macrophages co-cultured with high-metastatic-potential HCC cell line. MARCKS expression was identified as significantly correlated with outcome in multiple types of cancer, especially in HCC. High MARCKS expression level was associated with poorer overall survival (OS), Progress-free survival (PFS), and also with patient gender, race, hepatitis virus background, stage, grade, AJCC_T, and vascular invasion. MARCKS was positively associated with levels of T follicular helper cells (TFH) (R = .48, p < .001), T helper type 2 (Th2) cells (R = .47, p < .001), macrophages (R = .41, p ≤ .001), T helper cells (R = .40, p < .001), T helper type 1 (Th1) cells (R = .38, p < .001), T cells (R = .34, p < .001), NK CD56bright cells (R = .34, p < .001) and immature DC (iDC) (R = .33, p < .001), and negatively associated with levels of T helper 17 (Th17) cells. Also, MARCKS may influence the M2 polarization and immune escape. CONCLUSION The present study suggests that MARCKS on TAMs is associated with poor prognosis and immune cell infiltration in HCC.
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Affiliation(s)
- Xudong Ren
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yanqin Ju
- Department of Stomotology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chaoqun Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ran Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Haoting Sun
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Quanbao Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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21
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Calleja-Conde J, Echeverry-Alzate V, Bühler KM, Durán-González P, Morales-García JÁ, Segovia-Rodríguez L, Rodríguez de Fonseca F, Giné E, López-Moreno JA. The Immune System through the Lens of Alcohol Intake and Gut Microbiota. Int J Mol Sci 2021; 22:ijms22147485. [PMID: 34299105 PMCID: PMC8303153 DOI: 10.3390/ijms22147485] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023] Open
Abstract
The human gut is the largest organ with immune function in our body, responsible for regulating the homeostasis of the intestinal barrier. A diverse, complex and dynamic population of microorganisms, called microbiota, which exert a significant impact on the host during homeostasis and disease, supports this role. In fact, intestinal bacteria maintain immune and metabolic homeostasis, protecting our organism against pathogens. The development of numerous inflammatory disorders and infections has been linked to altered gut bacterial composition or dysbiosis. Multiple factors contribute to the establishment of the human gut microbiota. For instance, diet is considered as one of the many drivers in shaping the gut microbiota across the lifetime. By contrast, alcohol is one of the many factors that disrupt the proper functioning of the gut, leading to a disruption of the intestinal barrier integrity that increases the permeability of the mucosa, with the final result of a disrupted mucosal immunity. This damage to the permeability of the intestinal membrane allows bacteria and their components to enter the blood tissue, reaching other organs such as the liver or the brain. Although chronic heavy drinking has harmful effects on the immune system cells at the systemic level, this review focuses on the effect produced on gut, brain and liver, because of their significance in the link between alcohol consumption, gut microbiota and the immune system.
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Affiliation(s)
- Javier Calleja-Conde
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Victor Echeverry-Alzate
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
- Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Malaga University, 29010 Málaga, Spain;
- Universidad Nebrija, Campus Madrid-Princesa, 28015 Madrid, Spain
| | - Kora-Mareen Bühler
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Pedro Durán-González
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Jose Ángel Morales-García
- Instituto de Investigaciones Biomédicas (CSIC-UAM) “Alberto Sols” (CSIC-UAM), 28029 Madrid, Spain;
- Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Lucía Segovia-Rodríguez
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Fernando Rodríguez de Fonseca
- Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Malaga University, 29010 Málaga, Spain;
| | - Elena Giné
- Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Jose Antonio López-Moreno
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
- Correspondence:
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22
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A Combination of Geniposide and Chlorogenic Acid Combination Ameliorates Nonalcoholic Steatohepatitis in Mice by Inhibiting Kupffer Cell Activation. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6615881. [PMID: 34095305 PMCID: PMC8140849 DOI: 10.1155/2021/6615881] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/20/2021] [Accepted: 05/05/2021] [Indexed: 12/24/2022]
Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide. Activation of Kupffer cells (KCs) is central to the development of diet-induced NASH. We investigated whether a combination of two active chemical components, geniposide and chlorogenic acid (GC), at a specific ratio (67 : 1), ameliorates diet-induced NASH and the underlying mechanisms involved. C57BL/6J mice exposed to a high-fat and high-cholesterol (HFHC) diet containing cholesterol, choline, and high-sugar drinking water, as well as RAW264.7 cells stimulated with lipopolysaccharide (LPS) were studied. The combination exerted a therapeutic effect on HFHC-induced NASH in mice. Simultaneously, GC was found to reduce the expression of cytokines secreted by hepatic macrophages, including tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), IL-1β, IL-6, monocyte chemotactic protein 1 (MCP-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, GC reduced the number of KCs expressing F4/80. Furthermore, TNF-α, inducible nitric oxide synthase (INOS), IL-1β, and IL-6 mRNA and TNF-α protein expression levels were suppressed upon GC treatment in RAW264.7 cells. Our findings suggest that GC has a strong anti-inflammatory effect in NASH, and this effect can be attributed to the suppression of KC activity in the liver.
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23
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Martínez-Chantar ML, Delgado TC, Beraza N. Revisiting the Role of Natural Killer Cells in Non-Alcoholic Fatty Liver Disease. Front Immunol 2021; 12:640869. [PMID: 33679803 PMCID: PMC7930075 DOI: 10.3389/fimmu.2021.640869] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease. The histological spectrum of NAFLD ranges from simple steatosis to chronic inflammation and liver fibrosis during Non-Alcoholic Steatohepatitis (NASH). The current view is that innate immune mechanisms represent a key element in supporting hepatic inflammation in NASH. Natural Killer (NK) cells are lymphoid cells and a component of the innate immune system known to be involved in NASH progression. Increasing evidence has shed light on the differential function of circulating and tissue-resident NK cells, as well as on the relevance of metabolism and the microenvironment in regulating their activity. Here, we revisit the complex role of NK cells as regulators of NASH progression as well as potential therapeutic approaches based on their modulation.
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Affiliation(s)
- María Luz Martínez-Chantar
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance, Derio, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Spain
| | - Teresa C Delgado
- Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance, Derio, Spain
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich, United Kingdom
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24
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Buyco DG, Martin J, Jeon S, Hooks R, Lin C, Carr R. Experimental models of metabolic and alcoholic fatty liver disease. World J Gastroenterol 2021; 27:1-18. [PMID: 33505147 PMCID: PMC7789066 DOI: 10.3748/wjg.v27.i1.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/01/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This “syndrome of metabolic and alcoholic steatohepatitis” (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.
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Affiliation(s)
- Delfin Gerard Buyco
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Jasmin Martin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Royce Hooks
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Chelsea Lin
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
| | - Rotonya Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104, United States
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25
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Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol 2020; 18:73-91. [PMID: 33268887 PMCID: PMC7852578 DOI: 10.1038/s41423-020-00579-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.
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26
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Medeiros T, Saraiva GN, Moraes LA, Gomes AC, Lacerda GS, Leite PE, Esberard EB, Andrade TG, Xavier AR, Quírico-Santos T, Rosário NF, Silva AA. Liver fibrosis improvement in chronic hepatitis C after direct acting-antivirals is accompanied by reduced profibrogenic biomarkers-a role for MMP-9/TIMP-1. Dig Liver Dis 2020; 52:1170-1177. [PMID: 32522433 DOI: 10.1016/j.dld.2020.05.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/20/2020] [Accepted: 05/04/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Disturbances in matrix metalloproteinases (MMPs) and corresponding tissue inhibitors (TIMPs) contribute to hepatitis C virus (HCV)-induced fibrosis. This study aimed to determine MMP-9/TIMP-1 levels in addition to MMP-2 and -9 activities; correlating with the improvement of liver fibrosis in patients under direct-acting antiviral (DAA) therapy. METHODS Clinical and laboratory follow-up were performed before treatment and after 12 weeks post-treatment, referred as sustained viral response (SVR). We evaluated liver function including non-invasive fibrosis measurements; MMP activity by zymography; and MMP-9/TIMP-1 complex, inflammatory and pro-fibrogenic mediators by immunoenzymatic assays. RESULTS Cohort included 33 patients (59.5 ± 9.3 years, 60.6% females) whose reached SVR and 11 control-paired subjects (42.5 ± 15 years, 54.5% females). Before treatment, HCV patients presented higher MMP-9/TIMP-1 levels (P < 0.05) when compared to controls, and the highest values were observed in patients with fibrosis (P < 0.05). In addition, MMP-9/TIMP-1 levels were significantly reduced after DAA therapy (P < 0.0001) and were associated with profibrogenic biomarkers. No differences were observed for MMP-2 and -9 activities; however, these biomarkers were significantly associated with inflammatory mediators. CONCLUSION Our data suggest that MMP-9/TIMP-1 complex can be a promising biomarker of active fibrogenesis, being able to identify the interruption of fibrosis progression after HCV eradication.
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Affiliation(s)
- Thalia Medeiros
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | - Geórgia N Saraiva
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | - Laiz A Moraes
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil
| | - Aline C Gomes
- Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
| | - Gilmar S Lacerda
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | - Paulo Ec Leite
- Laboratório de Bioengenharia e Toxicologia in Vitro Diretoria de Metrologia Aplicada às Ciências da Vida - Dimav Instituto Nacional de Metrologia Qualidade e Tecnologia - INMETRO, Duque de Caxias, Rio de Janeiro, Brazil.
| | - Eliane Bc Esberard
- Centro de Referência de Tratamento em Hepatites/HUAP Serviço de Gastroenterologia Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil
| | - Thaís G Andrade
- Centro de Referência de Tratamento em Hepatites/HUAP Serviço de Gastroenterologia Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | - Analúcia R Xavier
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil; Departamento de Patologia Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | | | - Natalia F Rosário
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
| | - Andrea A Silva
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas Departamento de Medicina Clínica Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil; Departamento de Patologia Faculdade de Medicina, Universidade Federal Fluminense, Niterói, Brazil.
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27
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Moon JS, Goeminne LJE, Kim JT, Tian JW, Kim S, Nga HT, Kang SG, Kang BE, Byun J, Lee Y, Jeon J, Shong M, Auwerx J, Ryu D, Yi H. Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice. Aging Cell 2020; 19:e13195. [PMID: 32691494 PMCID: PMC7431835 DOI: 10.1111/acel.13195] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 06/19/2020] [Accepted: 06/23/2020] [Indexed: 12/28/2022] Open
Abstract
Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.
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Affiliation(s)
- Ji Sun Moon
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Ludger J. E. Goeminne
- Laboratory of Integrative Systems PhysiologyÉcole Polytechnique Fédérale de Lausanne (EPFL)LausanneSwitzerland
| | - Jung Tae Kim
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Jing Wen Tian
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Seok‐Hwan Kim
- Department of SurgeryChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Ha Thi Nga
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Seul Gi Kang
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Baeki E. Kang
- Department of Molecular Cell BiologySungkyunkwan University School of MedicineSuwonRepublic of Korea
| | - Jin‐Seok Byun
- Department of Oral MedicineSchool of DentistryKyungpook National UniversityDaeguRepublic of Korea
| | - Young‐Sun Lee
- Department of Internal MedicineKorea University College of MedicineSeoulRepublic of Korea
| | - Jae‐Han Jeon
- Department of Internal MedicineSchool of MedicineKyungpook National UniversityDaeguKorea
| | - Minho Shong
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
| | - Johan Auwerx
- Laboratory of Integrative Systems PhysiologyÉcole Polytechnique Fédérale de Lausanne (EPFL)LausanneSwitzerland
| | - Dongryeol Ryu
- Department of Molecular Cell BiologySungkyunkwan University School of MedicineSuwonRepublic of Korea
- Biomedical Institute for Convergence at SKKU (BICS)Sungkyunkwan UniversitySuwonRepublic of Korea
- Samsung Biomedical Research InstituteSamsung Medical CenterSeoulRepublic of Korea
| | - Hyon‐Seung Yi
- Research Center for Endocrine and Metabolic DiseasesChungnam National University HospitalChungnam National University School of MedicineDaejeonRepublic of Korea
- Department of Medical ScienceChungnam National University School of MedicineDaejeonRepublic of Korea
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28
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Ye L, He S, Mao X, Zhang Y, Cai Y, Li S. Effect of Hepatic Macrophage Polarization and Apoptosis on Liver Ischemia and Reperfusion Injury During Liver Transplantation. Front Immunol 2020; 11:1193. [PMID: 32676077 PMCID: PMC7333353 DOI: 10.3389/fimmu.2020.01193] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
Ischemia-reperfusion (I/R) injury is injury caused by a limited blood supply and subsequent blood supply recovery during liver transplantation. Serious ischemia-reperfusion injury is the main cause of transplant failure. Hepatic I/R is characterized by tissue hypoxia due to a limited blood supply and reperfusion inducing oxidative stress and an immune response. Studies have confirmed that Kupffer cells (KCs), resident macrophages in the liver, play a key role in aseptic inflammation induced by I/R. In liver macrophage polarization, M1 macrophages activated by interferon-γ (IFN-γ) and lipopolysaccharide (LPS) exert a pro-inflammatory effect and release a variety of inflammatory cytokines. M2 macrophages activated by IL-4 have an anti-inflammatory response. M1-type KCs are the dominant players in I/R as they secrete various pro-inflammatory cytokines that exacerbate the injury and recruit other types of immune cells via the circulation. In contrast, M2-type KCs can ameliorate I/R through unregulated anti-inflammatory factors. A new notion has been proposed that KC apoptosis may influence I/R in yet another manner as well. Management of KCs is expected to help improve I/R. This review summarizes the effects of hepatic macrophage polarization and apoptosis on liver I/R.
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Affiliation(s)
- Liping Ye
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Saiqin He
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.,Endoscopy Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yu Zhang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yue Cai
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shaowei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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Auguet T, Bertran L, Binetti J, Aguilar C, Martínez S, Sabench F, Lopez-Dupla JM, Porras JA, Riesco D, Del Castillo D, Richart C. Relationship between IL-8 Circulating Levels and TLR2 Hepatic Expression in Women with Morbid Obesity and Nonalcoholic Steatohepatitis. Int J Mol Sci 2020; 21:ijms21114189. [PMID: 32545403 PMCID: PMC7312372 DOI: 10.3390/ijms21114189] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/25/2022] Open
Abstract
The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.
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Affiliation(s)
- Teresa Auguet
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
- Correspondence: ; Tel.: +34-97-729-5833
| | - Laia Bertran
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Jessica Binetti
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Carmen Aguilar
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
| | - Salomé Martínez
- Hospital Universitari de Tarragona Joan XXIII, Servei Anatomia Patològica, 43007 Tarragona, Spain;
| | - Fàtima Sabench
- Hospital Universitari Sant Joan de Reus, Servei de Cirurgia, Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43204 Reus, Spain; (F.S.); (D.D.C.)
| | - Jesús Miguel Lopez-Dupla
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - José Antonio Porras
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - David Riesco
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
| | - Daniel Del Castillo
- Hospital Universitari Sant Joan de Reus, Servei de Cirurgia, Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43204 Reus, Spain; (F.S.); (D.D.C.)
| | - Cristóbal Richart
- Grup de Recerca GEMMAIR (AGAUR)-Medicina Aplicada (URV), Departament de Medicina i Cirurgia, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili (URV), 43007 Tarragona, Spain; (L.B.); (J.B.); (C.A.); (J.M.L.-D.); (J.A.P.); (C.R.)
- Hospital Universitari de Tarragona Joan XXIII, Servei Medicina Interna, 43007 Tarragona, Spain;
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Liu F, Qin L, Liao Z, Song J, Yuan C, Liu Y, Wang Y, Xu H, Zhang Q, Pei Y, Zhang H, Pan Y, Chen X, Zhang Z, Zhang W, Zhang B. Microenvironment characterization and multi-omics signatures related to prognosis and immunotherapy response of hepatocellular carcinoma. Exp Hematol Oncol 2020; 9:10. [PMID: 32509418 PMCID: PMC7249423 DOI: 10.1186/s40164-020-00165-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 05/19/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Immune cell infiltration in the tumor microenvironment (TME) affects tumor initiation, patients' prognosis and immunotherapy strategies. However, their roles and interactions with genomics and molecular processes in hepatocellular carcinoma (HCC) still have not been systematically evaluated. METHODS We performed unsupervised clustering of total 1000 HCC samples including discovery and validation group from available public datasets. Immune heterogeneity of each subtype was explored by multi-dimension analysis. And a support vector machine (SVM) model based on multi-omics signatures was trained and tested. Finally, we performed immunohistochemistry to verify the immune role of signatures. RESULTS We defined three immune subtypes in HCC, with diverse clinical, molecular, and genomic characteristics. Cluster1 had worse prognosis, better anti-tumor characteristics and highest immune scores, but also accompanied by immunosuppression and T cell dysfunction. Meanwhile, a better anti-PD1/CTLA4 immunotherapeutic response was predicted in cluster1. Cluster2 was enriched in TAM-M2 and stromal cells, indicating immunosuppression. Cluster3, with better prognosis, had lowest CD8 T cell but highest immune resting cells. Further, based on genomic signatures, we developed an SVM classifier to identify the patient's immunological status, which was divided into Type A and Type B, in which Type A had poorer prognosis, higher T cell dysfunction despite higher T cell infiltration, and had better immunotherapeutic response. At the same time, MMP9 may be a potential predictor of the immune characteristics and immunotherapeutic response in HCC. CONCLUSIONS Our work demonstrated 3 immune clusters with different features. More importantly, multi-omics signatures, such as MMP9 was identified based on three clusters to help us recognize patients with different prognosis and responses to immunotherapy in HCC. This study could further reveal the immune status of HCC and provide potential predictors for immune checkpoint treatment response.
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Affiliation(s)
- Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
- The Second Clinical Medicine College, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Lu Qin
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Chaoyi Yuan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Yachong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Yu Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Heze Xu
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Qiaofeng Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Youliang Pei
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Hongwei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Yonglong Pan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030 Hubei China
- Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, 430030 Hubei China
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Alpha-syntrophin deficiency protects against non-alcoholic steatohepatitis associated increase of macrophages, CD8 + T-cells and galectin-3 in the liver. Exp Mol Pathol 2019; 113:104363. [PMID: 31881201 DOI: 10.1016/j.yexmp.2019.104363] [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: 11/28/2019] [Revised: 12/18/2019] [Accepted: 12/24/2019] [Indexed: 11/22/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by immune cell infiltration. Loss of the scaffold protein alpha-syntrophin (SNTA) protected mice from hepatic inflammation in the methionine-choline-deficient (MCD) diet model. Here, we determined increased numbers of macrophages and CD8+ T-cells in MCD diet induced NASH liver of wild type mice. In the mutant animals these NASH associated changes in immune cell composition were less pronounced. Further, there were more γδ T-cells in the NASH liver of the null mice. Galectin-3 protein in the hepatic non-parenchymal cell fraction was strongly induced in MCD diet fed wild type but not mutant mice. Antioxidant enzymes declined in NASH liver with no differences between the genotypes. To identify the target cells responsive to SNTA loss in-vitro experiments were performed. In the human hepatic stellate cell line LX-2, SNTA did not regulate pro-fibrotic or antioxidant proteins like alpha-smooth muscle actin or catalase. Soluble galectin-3 was, however, reduced upon SNTA knock-down and increased upon SNTA overexpression. SNTA deficiency neither affected cell proliferation nor cell death of LX-2 cells. In the macrophage cell line RAW264.7 low SNTA indeed caused higher galectin-3 production whereas release of TNF and cell viability were normal. Moreover, SNTA had no effect on hepatocyte chemerin and CCL2 expression. Overall, SNTA loss improved NASH without causing major effects in macrophage, hepatocyte and hepatic stellate cell lines. SNTA null mice fed the MCD diet had less body weight loss and this seems to contribute to improved liver health of the mutant mice.
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Azad RK, Shulaev V. Metabolomics technology and bioinformatics for precision medicine. Brief Bioinform 2019; 20:1957-1971. [PMID: 29304189 PMCID: PMC6954408 DOI: 10.1093/bib/bbx170] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 11/29/2017] [Indexed: 12/14/2022] Open
Abstract
Precision medicine is rapidly emerging as a strategy to tailor medical treatment to a small group or even individual patients based on their genetics, environment and lifestyle. Precision medicine relies heavily on developments in systems biology and omics disciplines, including metabolomics. Combination of metabolomics with sophisticated bioinformatics analysis and mathematical modeling has an extreme power to provide a metabolic snapshot of the patient over the course of disease and treatment or classifying patients into subpopulations and subgroups requiring individual medical treatment. Although a powerful approach, metabolomics have certain limitations in technology and bioinformatics. We will review various aspects of metabolomics technology and bioinformatics, from data generation, bioinformatics analysis, data fusion and mathematical modeling to data management, in the context of precision medicine.
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Affiliation(s)
| | - Vladimir Shulaev
- Corresponding author: Vladimir Shulaev, Department of Biological Sciences, BioDiscovery Institute, University of North Texas, Denton, TX 76210, USA. Tel.: 940-369-5368; Fax: 940-565-3821; E-mail:
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Aflatoxin B1 enhances pyroptosis of hepatocytes and activation of Kupffer cells to promote liver inflammatory injury via dephosphorylation of cyclooxygenase-2: an in vitro, ex vivo and in vivo study. Arch Toxicol 2019; 93:3305-3320. [PMID: 31612242 DOI: 10.1007/s00204-019-02572-w] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022]
Abstract
Aflatoxin B1 (AFB1), a food contaminant derived from Aspergillus fungi, has been reported to cause hepatic immunotoxicity via inflammatory infiltration and cytokines release. As a pro-inflammatory factor, cyclooxygenase-2 (COX-2) is widely involved in liver inflammation induced by xenobiotics. However, the mechanism by which AFB1-induced COX-2 regulates liver inflammatory injury via hepatocytes-Kupffer cells (KCs) crosstalk remains unclear and requires further elucidation. Here, we established a COX-2 upregulated model with AFB1 treatment in vivo (C57BL/6 mice, 1 mg/kg body weight, i.g, 4 weeks) and in vitro (human liver HepaRG cells, 1 μM for 24 h). In vivo, AFB1-treated mice exhibited NLRP3 inflammasome activation, inflammatory infiltration, and increased recruitment of KCs. In vitro, dephosphorylated COX-2 by protein phosphatase 2A (PP2A)-B55δ promoted NLRP3 inflammasome activation, including mitochondrial translocation of NLRP3, caspase 1 cleavage, and IL-1β release. Moreover, phosphorylated COX-2 at serine 601 (p-COX-2Ser601) underwent endoplasmic reticulum (ER) retention for proteasome degradation. Furthermore, pyroptosis and inflammatory response induced by AFB1 were relieved with COX-2 genetic (siPTGS2) intervention or pharmaceutic (celecoxib, 30 mg/kg body weight, i.g, 4 weeks) inhibition of COX-2 via NLRP3 inflammasome suppression in vivo and in vitro. Ex vivo, in a co-culture system with murine primary hepatocytes and KCs, activated KCs induced by damaged signals from pyroptotic hepatocytes, formed a feedback loop to amplify NLRP3-dependent pyroptosis of hepatocytes via pro-inflammatory signaling, leading to liver inflammatory injury. Taken together, our data suggest a novel mechanism that protein quality control of COX-2 determines the intracellular distribution and activation of NLRP3 inflammasome, which promotes liver inflammatory injury via hepatocytes-KCs crosstalk.
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Yuan Y, Che L, Qi C, Meng Z. Protective effects of polysaccharides on hepatic injury: A review. Int J Biol Macromol 2019; 141:822-830. [PMID: 31487518 DOI: 10.1016/j.ijbiomac.2019.09.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 08/26/2019] [Accepted: 09/01/2019] [Indexed: 12/12/2022]
Abstract
Chronic hepatic injury caused by hepatitis B and C virus (HBV and HCV) infection, high fat diet and alcohol intake has increased to be the critical promoter of hepatocellular carcinoma (HCC). These high risk factors set into motion a vicious cycle of hepatocyte death, inflammation and fibrosis that finally results in cirrhosis and HCC after several decades. However, the treatment options for HCC are very limited. Therefore, early treatment of liver injury may reduce the incidence and probability of HCC or delay the progression of HCC. Substantial ongoing research has focused on nontoxic biological macromolecules, mainly polysaccharides, which possess prominent efficacies on hepatoprotective activity. Based on these encouraging observations, a great deal of effort has been devoted to discovering novel polysaccharides for the development of effective therapeutics for hepatic injury. This review focuses on the protective effects of polysaccharides on liver injury, including hepatitis virus infection, nonalcoholic steatohepatitis, alcoholic liver disease and other hepatic injuries, and describes the underlying mechanisms.
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Affiliation(s)
- Ye Yuan
- Department of Medicine Laboratory, First Hospital, Jilin University, Changchun 130021, China
| | - Lihe Che
- Department of Infectious Disease, First Hospital, Jilin University, Changchun 130021, China
| | - Chong Qi
- Department of Translational Medicine Research Institute, First Hospital, Jilin University, Changchun, Jilin 130021, China
| | - Zhaoli Meng
- Department of Translational Medicine Research Institute, First Hospital, Jilin University, Changchun, Jilin 130021, China.
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Zhu M, Li M, Zhou W, Yang Y, Li F, Zhang L, Ji G. Qianggan extract improved nonalcoholic steatohepatitis by modulating lncRNA/circRNA immune ceRNA networks. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:156. [PMID: 31269941 PMCID: PMC6609373 DOI: 10.1186/s12906-019-2577-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 06/25/2019] [Indexed: 01/01/2023]
Abstract
Background The traditional Chinese medicine prescription, Qianggan formula have been confirmed to be effective on non-alcoholic steatohepatitis (NASH), however, the underlying molecular mechanisms remain obscure. Methods Thirty-six male C57BL/6 mice were randomly divided into three groups: normal chow diet group; methionine-and-choline-deficient diet (MCD) group, and Qianggan extract (QG) intervention group (0.4 g/kg daily) that fed with MCD. The efficacy of QG was biochemically and histologically evaluated. The expression profiles of messenger ribonucleic acids (mRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) were examined using microarray and verified by RT-qPCR. Results QG significantly improved the phenotypic characteristics of NASH, as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) levels and liver inflammatory cytokines were significantly decreased. By the cutoff of a 1.5-fold change and P < 0.05, 6193 mRNAs, 5692 lncRNAs and 4843 circRNAs were identified as differentially expressed between the MCD and normal groups, and 514 mRNAs, 1182 lncRNAs and 443 circRNAs were identified as differentially expressed between the QG and MCD groups. The intersections (244 mRNAs, 259 lncRNAs and 98 circRNAs) among the three groups were chosen for analysis. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that most overlapping mRNAs were related to immune functions such as natural-killer-cell-mediated cytotoxicity, intestinal immune network for IgA production, and T cell receptor signaling pathway. Pathway interactions, protein-protein interactions and molecular complex detection (MCODE) analysis identified numerous immune-related hub genes e.g. natural cytotoxicity triggering receptor 1(Ncr1), C-X-C motif chemokine ligand 9 (Cxcl9), Klra1, and Cd28. Finally, two lncRNAs (Sngh1 and Slc36a3os) and four circRNAs (circ_0009029, circ_0004572, circ_0009212 and circ_0009453) in competing endogenous RNA (ceRNA) networks were constructed by Cytoscape, and immune-related mRNAs (e.g., Cd28, Cd8a, Il15, and Klrk1) were involved in the ceRNA networks. Conclusions LncRNA and circRNA-associated immune ceRNA networks might be the targets of QG in alleviating NASH, and our work may provide valuable clues for exploring the mechanisms underlying the effect of QG. Electronic supplementary material The online version of this article (10.1186/s12906-019-2577-6) contains supplementary material, which is available to authorized users.
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Li S, Tan HY, Wang N, Feng Y, Wang X, Feng Y. Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease. Front Immunol 2019; 10:1328. [PMID: 31244862 PMCID: PMC6581703 DOI: 10.3389/fimmu.2019.01328] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/24/2019] [Indexed: 12/12/2022] Open
Abstract
Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.
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Affiliation(s)
- Sha Li
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Hor-Yue Tan
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Ning Wang
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Yigang Feng
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Laboratory of Wudang Local Chinese Medicine Research, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- Li Ka Shing Faculty of Medicine, School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
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Innate immune regulatory networks in hepatic lipid metabolism. J Mol Med (Berl) 2019; 97:593-604. [PMID: 30891617 DOI: 10.1007/s00109-019-01765-1] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/06/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
Abstract
Hepatic lipid metabolism is closely associated with certain diseases, such as obesity, diabetes, fatty liver, and hepatic fibrosis. Hepatic steatosis results from systemic metabolic dysfunction that occurs via multiple processes. The initial process has been characterized as hepatic lipid accumulation that may be caused by increased liver lipid uptake and de novo lipogenesis or decreased lipid oxidation and lipid export; subsequently, multiple additional factors that trigger inflammation and insulin resistance (IR) aggravate the progression of hepatic steatosis. Emerging evidence indicates that inflammation stands at the crossroads of innate immunity and lipid metabolism and links the initial metabolic stress and subsequent metabolic events in lipid metabolism. Therefore, in this review, we summarize the regulatory role of innate immune signaling molecules in maintaining lipid metabolic homeostasis; these revelations can guide the development of potential therapies for nonalcoholic fatty liver disease (NAFLD).
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Yi HS, Kim SY, Kim JT, Lee YS, Moon JS, Kim M, Kang YE, Joung KH, Lee JH, Kim HJ, Chun K, Shong M, Ku BJ. T-cell senescence contributes to abnormal glucose homeostasis in humans and mice. Cell Death Dis 2019; 10:249. [PMID: 30867412 PMCID: PMC6416326 DOI: 10.1038/s41419-019-1494-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/26/2019] [Accepted: 02/28/2019] [Indexed: 02/06/2023]
Abstract
Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.
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Affiliation(s)
- Hyon-Seung Yi
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. .,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.
| | - So Yeon Kim
- Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, Korean Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.,Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Jung Tae Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Medical Science, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, 35015, Republic of Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, 08308, Republic of Korea
| | - Ji Sun Moon
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Mingyo Kim
- Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, 79, Gangnam-ro, Jinju, Gyeongnam, 660-702, Republic of Korea
| | - Yea Eun Kang
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Kyong Hye Joung
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Ju Hee Lee
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Hyun Jin Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Kwangsik Chun
- Department of Surgery, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Minho Shong
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Bon Jeong Ku
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea. .,Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.
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Ambade A, Lowe P, Kodys K, Catalano D, Gyongyosi B, Cho Y, Vellve AI, Adejumo A, Saha B, Calenda C, Mehta J, Lefebvre E, Vig P, Szabo G. Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice. Hepatology 2019; 69:1105-1121. [PMID: 30179264 PMCID: PMC6393202 DOI: 10.1002/hep.30249] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 08/17/2018] [Indexed: 12/17/2022]
Abstract
Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MØ in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.
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Affiliation(s)
- Aditya Ambade
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Patrick Lowe
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Benedek Gyongyosi
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Yeonhee Cho
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Arvin-Iracheta Vellve
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Adeyinka Adejumo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Banishree Saha
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Charles Calenda
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Jeeval Mehta
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | | | - Pamela Vig
- Allergan plc, South San Francisco, CA, 94080, USA
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.,Contact Information: Gyongyi Szabo, MD, PhD, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA, 01605, USA., Tel: 1-508-856-5276, Fax: 1-528-856-5033,
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Liang Q, Liu Z, Zhu C, Wang B, Liu X, Yang Y, Lv X, Mu H, Wang K. Intrahepatic T-Cell Receptor β Immune Repertoire Is Essential for Liver Regeneration. Hepatology 2018; 68:1977-1990. [PMID: 29704254 DOI: 10.1002/hep.30067] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/27/2018] [Accepted: 04/24/2018] [Indexed: 12/18/2022]
Abstract
T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T-cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High-throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRβ immune repertoire in liver regeneration (LR). We investigated hepatic regeneration in TCRβ chain-deficient (tcrb-/- ) mice by two-thirds partial hepatectomy (PHx) method. Our results demonstrated that tcrb-/- mice revealed a reduced capacity for LR, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signaling activation and inflammatory factors was observed in regenerated tcrb-/- livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRβ immune repertoire during LR, indicating that PHx resulted in remarkably lower TCRβ diversity in intrahepatic T lymphocytes. Conclusion: Taken together, our data suggest that TCRβ deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs LR, and the TCRβ reconstitution is required for hepatic immunocyte recruitment and activation during LR.
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Affiliation(s)
- Qing Liang
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Zeyuan Liu
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Chao Zhu
- Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Bin Wang
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiaoke Liu
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Yanan Yang
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Xue Lv
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Haiyu Mu
- College of Basic Medicine, Qingdao University, Qingdao, China
| | - Kejia Wang
- College of Basic Medicine, Qingdao University, Qingdao, China
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Primary rat LSECs preserve their characteristic phenotype after cryopreservation. Sci Rep 2018; 8:14657. [PMID: 30279440 PMCID: PMC6168544 DOI: 10.1038/s41598-018-32103-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 07/31/2018] [Indexed: 02/08/2023] Open
Abstract
Liver disease is a leading cause of morbidity and mortality worldwide. Recently, the liver non-parenchymal cells have gained increasing attention for their potential role in the development of liver disease. Liver sinusoidal endothelial cells (LSECs), a specialized type of endothelial cells that have unique morphology and function, play a fundamental role in maintaining liver homeostasis. Current protocols for LSEC isolation and cultivation rely on freshly isolated cells which can only be maintained differentiated in culture for a few days. This creates a limitation in the use of LSECs for research and a need for a consistent and reliable source of these cells. To date, no LSEC cryopreservation protocols have been reported that enable LSECs to retain their functional and morphological characteristics upon thawing and culturing. Here, we report a protocol to cryopreserve rat LSECs that, upon thawing, maintain full LSEC-signature features: fenestrations, scavenger receptor expression and endocytic function on par with freshly isolated cells. We have confirmed these features by a combination of biochemical and functional techniques, and super-resolution microscopy. Our findings offer a means to standardize research using LSECs, opening the prospects for designing pharmacological strategies for various liver diseases, and considering LSECs as a therapeutic target.
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