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Zhang C, Jiao S, Zeng D, Jiang W, Wang R, Zheng B, Wang M, Wang S, Gui X. IL-11/IL-11R signal inhibition by 9MW3811 remodels immune tumor microenvironment and enhances anti-tumor efficacy of PD-1 blockade. NPJ Precis Oncol 2025; 9:138. [PMID: 40355638 PMCID: PMC12069607 DOI: 10.1038/s41698-025-00913-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 04/14/2025] [Indexed: 05/14/2025] Open
Abstract
Recent studies have uncovered evidences for pro-tumorigenic activities attributed to IL-11, prompting a renewed focus on therapeutic strategies targeting IL-11 signaling for anti-tumor treatment. Here, we introduce 9MW3811, a monoclonal antibody designed to neutralize IL-11 effectively. By disrupting the IL-11/IL-11Rα/gp130 complex, 9MW3811 inhibits JAK/STAT3 signaling, significantly reducing tumor growth in diverse mouse models. More importantly, 9MW3811 synergizes with anti-PD-1 therapy, even in PD-1 non-responsive models like CT26. Single-cell RNA-seq analysis reveals that 9MW3811 remodels the tumor microenvironment by enhancing CD8+ T cell infiltration and reversing T cell exhaustion via upregulated XCL1 and downregulated CCL7, boosting anti-tumor cytotoxicity. Furthermore, 9MW3811 counteracts PD-1-induced T cell exhaustion, with anti-PD-1 antibodies effectively mitigating PD-1 upregulation post-9MW3811 treatment. These compelling findings support ongoing clinical trials of 9MW3811, aiming to translate these preclinical insights into therapeutic benefits for cancer patients.
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Affiliation(s)
- Chang Zhang
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
- Beijing Kohnoor Science & Technology Co. Ltd., 102206, Beijing, China
| | - Shasha Jiao
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
- Beijing Kohnoor Science & Technology Co. Ltd., 102206, Beijing, China
| | - Dadi Zeng
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
- Beijing Kohnoor Science & Technology Co. Ltd., 102206, Beijing, China
| | - Wen Jiang
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
| | - Rongjuan Wang
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
- Beijing Kohnoor Science & Technology Co. Ltd., 102206, Beijing, China
| | - Bin Zheng
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
| | - Min Wang
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China
| | - Shuang Wang
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China.
- Beijing Kohnoor Science & Technology Co. Ltd., 102206, Beijing, China.
| | - Xun Gui
- Mabwell (Shanghai) Bioscience Co. Ltd., 201210, Shanghai, China.
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2
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Chen X, Zou G, Yang Z, Qi X, Song F, Peng L, Wang D, Zhou J, Ma J, He H, Hong Y, Wang YE, Fan Y, Liu Z, Li X. Serum metabolomic profiling uncovered metabolic shifts in individuals upon moderate-altitude exposure and identified the potentiality of beta-alanine to ameliorate hyperuricemia. Redox Biol 2025; 81:103546. [PMID: 40058067 PMCID: PMC11930757 DOI: 10.1016/j.redox.2025.103546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Accepted: 02/11/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND High-altitude exposure has been associated with an increased risk of hyperuricemia (HU) and gout, though the underlying mechanisms remain poorly understood. METHODS We conducted a comprehensive analysis of the serum metabolome and phenome in both discovery and validation cohorts of Han Chinese individuals who underwent long-term moderate-altitude exposure (∼12 months), as well as in an independent cohort consisting of local Han Chinese and Tibetans residing in Nyingchi (>5 years). Beta-Alanine intervention was applied in hypoxanthine and potassium oxonate-induced in vitro and in vivo experiments. RESULTS Individuals exposed to moderate altitude exhibited elevated serum urate and an increase in overall medium-chain fatty acids (MCFAs), coupled with a decrease in overall amino acids (AAs) and short-chain fatty acids (SCFAs). Rmcorr correlation analysis revealed a significant negative association between Beta-Alanine and serum urate, whereas nonanoic acid was in versa, potentially driving lower serum urate in long-term exposed residents. Both in vitro and in vivo experiments demonstrated that Beta-Alanine inhibited xanthine oxidase (XOD) and reversed the HU phenotype in human hepatocytes and mice induced by hypoxanthine (HX) and potassium oxonate (PO), with a urate-lowering effect in mice. Hepatic pathology and transcriptome analysis of HU mice treated with Beta-Alanine indicated that the mechanisms involved the inhibition of XOD, amelioration of the inflammation phenotype in hepatocytes, and promotion of renal urate excretion. Furthermore, the 10-fold cross-validation random forest classification (RFC) predictive modeling based on selected metabolites and phenotypes achieved an area under receiver operating characteristic (ROC) curve (AUC) value of 0.93 (95 % confidence interval (CI): 0.85-1.00) and 0.79 (95 % CI: 0.59-0.98) for distinguishing individuals with high risk of asymptomatic HU (AHU) in the training dataset and validation dataset, respectively. CONCLUSIONS This study reveals serum urate and metabolome altered in moderate-altitude exposed individuals and Beta-Alanine intervention could ameliorate hyperuricemia. Our findings suggest that targeting the circulating metabolome may pave novel avenues to counter diseases associated with HU.
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Affiliation(s)
- Xuanfu Chen
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China; Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Guoxiang Zou
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhibo Yang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xin Qi
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Feier Song
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Long Peng
- Department of Neurosurgery, Guangdong Provincial People's Hospital Ganzhou Hospital, China
| | - Dingchen Wang
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China
| | - Jingyan Zhou
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second Clinical School of Medicine, Southern Medical University, Guangzhou, China
| | - Jiahui Ma
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Haiwei He
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yimei Hong
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yu-E Wang
- Nyingchi People's Hospital, Tibet, China
| | - Yanqun Fan
- Biotree Metabolomics Technology Research Center, Shanghai, China.
| | - Zhipeng Liu
- Biotree Metabolomics Technology Research Center, Shanghai, China.
| | - Xin Li
- Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Nyingchi People's Hospital, Tibet, China.
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Xu H, Wu Z, Qin J, Li X, Xu F, Wang W, Zhang H, Yin H, Zhu S, Zhang W, Yang Y, Wei Y, Gao L, Liu J, Gao Y, Zheng MH, Zhou H, Qi T, Chen J, Gao Y, Zuo L, Chen J, Liangpunsakul S, Li J, Wang H. Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2. Gut 2025:gutjnl-2024-334318. [PMID: 40139745 DOI: 10.1136/gutjnl-2024-334318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/05/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear. OBJECTIVE We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte-neutrophil interaction and its impact on AH progression. DESIGN We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies. RESULTS RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2-deficient mice but was exacerbated in mice with hepatic overexpression of Lect2. Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury. CONCLUSION Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2-PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Zihao Wu
- Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei, Anhui, China
| | - Jiangfeng Qin
- Department of Infectious Diseases, the People's Hospital of Xuancheng City, Xuancheng, Anhui, China
| | - Xutong Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Feng Xu
- Department of Intensive Care Unit & Central Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Wei Wang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hui Zhang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
| | - HeHe Yin
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
| | - Shiwei Zhu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Yuanru Yang
- Department of Blood Transfusion, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, Beijing, China
| | - Yuanyuan Wei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Long Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jiatao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
| | - Haoxiong Zhou
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Tingting Qi
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, China
| | - Jinjun Chen
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, China
- Hepatology Unit, Department of Infectious Diseases, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Jiong Chen
- State Key Laboratory for Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, 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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Cao S, Yang L, Wang X, Yang W, Tang F, Tang S, Liu J. Unveiling causal relationships between addiction phenotypes and inflammatory cytokines: insights from bidirectional mendelian randomization and bibliometric analysis. Eur Arch Psychiatry Clin Neurosci 2025; 275:473-485. [PMID: 39327304 DOI: 10.1007/s00406-024-01915-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024]
Abstract
Observational studies have suggested associations between multiple inflammatory factors and tobacco and alcohol use, but establishing causation is challenging in epidemiological investigations. We employed genetic association data about the circulating levels of 41 cytokines obtained from the genome-wide association study (GWAS), which contained 8293 Finnish participants. Genetic data on 5 substance use phenotypes were obtained from the GWAS dataset containing 1.2 million European subjects. Then, we conducted a bidirectional mendelian randomization (MR) study. The forward results indicated that smoking cessation was positively correlated with hepatocyte growth factor (HGF), interleukin-10 (IL-10), and stem cell factor (SCF); cigarettes per day was a risk factor associated with high expression in stromal cell-derived factor 1α (SDF-1 A), interferon-γ (IFN-G), IL-4, and granulocyte colony-stimulating factor (G-CSF); drinks per week and smoking initiation were risk factors respectively correlated with reduced HGF and IL-2RA levels. During inverse MR analysis, the findings revealed that both IL-16 and IL-18 increased the risk of cigarettes per day; macrophage inflammatory protein-1β (MIP-1B) and tumor necrosis factor-β (TNF-B) inhibited and promoted smoking cessation, respectively; macrophage colony-stimulating factor (M-CSF) elevated the risk of drinks per week, while interferon inducible protein 10 (IP-10) had a contrary role; IL-7 and M-CSF respectively prolonged and shortened age of initiation of regular smoking. This study provides genetic proof supporting a causal relationship between various inflammatory factors and addiction phenotypes. Further comprehensive investigations are required to uncover underlying biological mechanisms. In addition, bibliometric studies have shown that oxidative stress is one of the most important orientations in alcohol and tobacco addiction research, where an in-depth investigation of its pro-inflammatory mechanisms would facilitate the development of potential therapeutic biological targets and drugs.
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Affiliation(s)
- Shirui Cao
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Longtao Yang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xuemei Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wenhan Yang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Fei Tang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shixiong Tang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China.
- Clinical Research Center for Medical Imaging in Hunan Province, Changsha, China.
- Department of Radiology Quality Control Center in Hunan Province, Changsha, China.
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5
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Zheng H, Zhong ZJ, Wang YC, Sun YB, Li FF. Downregulation of interleukin 11 regulates the transforming growth factor-β/ERK1/2 signaling pathway to inhibit articular capsule fibrosis and alleviate post-traumatic articular capsule contracture. J Shoulder Elbow Surg 2025; 34:584-594. [PMID: 39089417 DOI: 10.1016/j.jse.2024.05.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 05/26/2024] [Accepted: 05/31/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND Post-traumatic capsular contracture is a common complication of joint injury and surgery. Post-traumatic capsular contracture is associated with fibrosis characterized by excessive differentiation and proliferation of myofibroblasts and abnormal secretion and accumulation of extracellular matrix. Previous studies have suggested that interleukin 11 (IL11) plays a role in myocardial fibrosis. We thus hypothesized that IL11 may play a fibrotic role during capsular contracture, in order to discover new targets for preventing joint capsule contracture. METHODS We constructed a post-traumatic contracture model by excessively extending the knee joint and fixing the joint in the flexion position, and a post-traumatic joint capsule contracture model was constructed in the wild-type, IL11-/-, IL11 R -/-, α-SMA-cre-IL11fl/fl, α-SMA-cre-IL11Rfl/fl mouse strain, with wild-type mice without any treatment of the knee joint as the control group. Fibrotic markers and the expression of IL11 and IL11 R in knee joint tissue were detected in each group of mice. The NIH3T3 cell line was used for in vitro analyses. The expression of fibrosis markers, IL11, transforming growth factor-β, and ERK1/2 were detected by western blot, enzyme-linked immunosorbent assay, and real time quantitative polymerase chain reaction. RESULTS Inhibition of IL11 inhibited ERK1/2 phosphorylation, reduced the secretion of collagen in the joint capsule, and inhibited the excessive differentiation and proliferation of myofibroblasts in the post-traumatic joint capsule contracture, thus alleviating the joint capsule contracture and obtaining better joint mobility. CONCLUSION Downregulation of IL11 in traumatic joint capsule contracture inhibits ERK1/2 phosphorylation, thus significantly relieving joint capsule contracture. Our findings indicate the transforming growth factor-β/IL11/ERK1/2 axis is an important pathway for the differentiation of fibroblasts into myofibroblasts. Anti-IL11 treatment is an effective means to prevent traumatic joint capsule contracture.
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Affiliation(s)
- Heng Zheng
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Zhen-Jia Zhong
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yi-Chong Wang
- The 7th People's Hospital of Zhengzhou, Zhengzhou, China
| | - Yang-Bai Sun
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Feng-Feng Li
- Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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6
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Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
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7
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Tsuchiya Y, Nishina T, Komazawa-Sakon S, Seki T, Mikami T, Nakano H. Interleukin-11 signaling plays limited roles for liver fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis. Biochem Biophys Res Commun 2024; 739:150938. [PMID: 39536410 DOI: 10.1016/j.bbrc.2024.150938] [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: 10/29/2024] [Revised: 10/30/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Liver fibrosis, an abnormal accumulation of collagen fibers in the liver, is caused due to several chronic liver diseases including viral hepatitis, alcoholic steatohepatitis, and metabolic dysfunction-associated steatohepatitis. Among the various symptoms of chronic hepatitis, liver fibrosis is the most crucial factor in determining patient prognosis. Extensive liver fibrosis leads to cirrhosis and liver cancer and shortens the lifespans of patients. However, no drug is currently approved for the treatment of liver fibrosis. Therefore, the identification of molecular mechanisms and druggable targets of liver fibrosis is urgently needed. Interleukin-11 is a member of the interleukin-6 family of inflammatory cytokines that is involved in multiple processes of inflammation and tissue repair. Recent reports also suggest the pro-fibrogenic function of interleukin-11 in various organs. In this study, we examined the fibrogenic potential of interleukin-11 in the liver using a choline-deficient, amino acid-defined high-fat diet, a mouse model of metabolic dysfunction-associated steatohepatitis that rapidly develops liver fibrosis. Although interleukin-11 was specifically upregulated in the liver in this pathological model, the loss of interleukin-11 signaling played minor roles in liver injury, inflammation, fibrosis, and signal transduction pathways. Our results indicate that the pro-fibrogenic function of interleukin-11 may vary among organs and disease etiologies.
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Affiliation(s)
- Yuichi Tsuchiya
- Department of Biochemistry, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi-shi, Chiba, 274-8510, Japan.
| | - Takashi Nishina
- Department of Biochemistry, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Sachiko Komazawa-Sakon
- Department of Biochemistry, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Takao Seki
- Department of Biochemistry, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Tetuo Mikami
- Department of Pathology, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Hiroyasu Nakano
- Department of Biochemistry, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
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8
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Fu Y, Maccioni L, Wang XW, Greten TF, Gao B. Alcohol-associated liver cancer. Hepatology 2024; 80:1462-1479. [PMID: 38607725 DOI: 10.1097/hep.0000000000000890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024]
Abstract
Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
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Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Tim F Greten
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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9
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Gao C, Wang S, Xie X, Ramadori P, Li X, Liu X, Ding X, Liang J, Xu B, Feng Y, Tan X, Wang H, Zhang Y, Zhang H, Zhang T, Mi P, Li S, Zhang C, Yuan D, Heikenwalder M, Zhang P. Single-cell Profiling of Intrahepatic Immune Cells Reveals an Expansion of Tissue-resident Cytotoxic CD4 + T Lymphocyte Subset Associated With Pathogenesis of Alcoholic-associated Liver Diseases. Cell Mol Gastroenterol Hepatol 2024; 19:101411. [PMID: 39349248 PMCID: PMC11719870 DOI: 10.1016/j.jcmgh.2024.101411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND & AIMS The immunological mechanisms underpinning the pathogenesis of alcoholic-associated liver disease (ALD) remain incompletely elucidated. This study aims to explore the transcriptomic profiles of hepatic immune cells in ALD compared with healthy individuals and those with metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS We utilized single-cell RNA sequencing to analyze liver samples from healthy subjects and patients with MASLD and ALD, focusing on the immune cell landscapes within the liver. Key alterations in immune cell subsets were further validated using liver biopsy samples from additional patient cohorts. RESULTS We observed a significant accumulation of CD4+ T cells in livers of patients with ALD, surpassing the prevalence of CD8+ T cells, in contrast to patients with MASLD and healthy counterparts, whereas natural killer (NK) cells and γδT cells exhibited reduced intrahepatic infiltration. In-depth transcriptional and developmental trajectory analyses unveiled that a distinct CD4+ subset characterized by granzyme K (GZMK) expression, displaying a tissue-resident signature and terminal effector state, prominently enriched among CD4+ T cells infiltrating the livers of patients with ALD. Subsequent examination of an independent ALD patient cohort corroborated the substantial enrichment of GZMK+CD4+ T lymphocytes, primarily within liver fibrotic zones, suggesting their potential involvement in disease progression. Additionally, we noted shifts in myeloid populations, with expanded APOE+ macrophage and FCGR3B+ monocyte subsets in ALD samples relative to MASLD and healthy tissues. CONCLUSIONS In summary, this study unravels the intricate cellular diversity within hepatic immune cell populations, highlighting the pivotal immune pathogenic role of the GZMK+CD4+ T lymphocyte subset in ALD pathogenesis.
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Affiliation(s)
- Chao Gao
- Department of Hepatobiliary Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shiguan Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyu Xie
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Pierluigi Ramadori
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany
| | - Xinying Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyu Liu
- Advanced Medical Research Institute, Shandong University, Jinan, Shandong, China
| | - Xue Ding
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jinyuan Liang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Bowen Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yawei Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xueying Tan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Haoran Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Haiyan Zhang
- Department of Biochemistry, Heze Medical College, Heze, Shandong, China
| | - Tingguo Zhang
- Institute of Pathology and Pathophysiology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ping Mi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Shiyang Li
- Advanced Medical Research Institute, Shandong University, Jinan, Shandong, China
| | - Cuijuan Zhang
- Institute of Pathology and Pathophysiology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Tübingen, Germany.
| | - Peng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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Du HX, Yue SY, Niu D, Liu XH, Li WY, Wang X, Chen J, Hu DK, Zhang LG, Guan Y, Ji DX, Chen XG, Zhang L, Liang CZ. Alcohol intake exacerbates experimental autoimmune prostatitis through gut microbiota driving cholesterol biosynthesis-mediated Th17 differentiation. Int Immunopharmacol 2024; 139:112669. [PMID: 39029231 DOI: 10.1016/j.intimp.2024.112669] [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: 04/28/2024] [Revised: 06/30/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024]
Abstract
BACKGROUND Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is very common worldwide, and alcohol consumption is a notable contributing factor. Researches have shown that gut microbiota can be influenced by alcohol consumption and is an important mediator in regulating Th17 cell immunity. However, it is still unclear the exact mechanism by which alcohol exacerbates the CP/CPPS and the role of gut microbiota in this process. METHOD We first constructed the most-commonly used animal model for CP/CPPS, the experimental autoimmune prostatitis (EAP) model, through immunoassay. Based on this, mice were divided into EAP group and alcohol-consuming EAP group. By 16S rRNA sequencing and non-targeted metabolomics analysis, differential gut microbiota and their metabolites between the two groups were identified. Subsequently, metabolomics detection targeting cholesterols was carried out to identify the exact difference in cholesterol. Furthermore, multiple methods such as flow cytometry and immunohistochemistry were used to detect the differentiation status of Th17 cells and severity of prostatitis treated with 27-hydroxycholesterol (the differential cholesterol) and its upstream regulatory factor-sterol regulatory element-binding protein 2 (SREBP2). Lastly, fecal transplantation was conducted to preliminary study on whether alcohol intake exacerbates EAP in immune receptor mice. RESULTS Alcohol intake increased the proportion of Th17 cells and levels of related inflammatory factors. It also led to an altered gut bacterial richness and increased gut permeability. Further metabolomic analysis showed that there were significant differences in a variety of metabolites between EAP and alcohol-fed EAP mice. Metabolic pathway enrichment analysis showed that the pathways related to cholesterol synthesis and metabolism were significantly enriched, which was subsequently confirmed by detecting the expression of metabolic enzymes. By targeting cholesterol synthesis, 27-hydroxycholesterol was significantly increased in alcohol-fed EAP mice. Subsequent mechanistic research showed that supplementation with 27-hydroxycholesterol could aggravate EAP and promote Th17 cell differentiation both in vivo and in vitro, which is regulated by SREBP2. In addition, we observed that fecal transplantation from mice with alcohol intake aggravated EAP in immunized recipient mice fed a normal diet. CONCLUSION Our study is the first to show that alcohol intake promotes Th17 cell differentiation and exacerbates EAP through microbiota-derived cholesterol biosynthesis.
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Affiliation(s)
- He-Xi Du
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Shao-Yu Yue
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Di Niu
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Xian-Hong Liu
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Wei-Yi Li
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Xu Wang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Jia Chen
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - De-Kai Hu
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Li-Gang Zhang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Yu Guan
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China
| | - Duo-Xu Ji
- Clinical Medical College, Anhui Medical University, Hefei, Anhui, PR China
| | - Xian-Guo Chen
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China.
| | - Li Zhang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China.
| | - Chao-Zhao Liang
- Department of Urology, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, PR China; Institute of Urology, Anhui Medical University, Hefei, Anhui, PR China; Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, PR China.
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Feng Z, Zhou B, Shuai Q, Wei Y, Jin N, Wang X, Zhao H, Liu Z, Xu J, Mu J, Xie J. Development of an alcoholic liver disease model for drug evaluation from human induced pluripotent stem cell-derived liver organoids. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1460-1472. [PMID: 38818583 PMCID: PMC11532202 DOI: 10.3724/abbs.2024074] [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: 01/22/2024] [Accepted: 03/07/2024] [Indexed: 06/01/2024] Open
Abstract
Alcoholic liver disease (ALD) poses a significant health challenge, so comprehensive research efforts to improve our understanding and treatment strategies are needed. However, the development of effective treatments is hindered by the limitation of existing liver disease models. Liver organoids, characterized by their cellular complexity and three-dimensional (3D) tissue structure closely resembling the human liver, hold promise as ideal models for liver disease research. In this study, we use a meticulously designed protocol involving the differentiation of human induced pluripotent stem cells (hiPSCs) into liver organoids. This process incorporates a precise combination of cytokines and small molecule compounds within a 3D culture system to guide the differentiation process. Subsequently, these differentiated liver organoids are subject to ethanol treatment to induce ALD, thus establishing a disease model. A rigorous assessment through a series of experiments reveals that this model partially recapitulates key pathological features observed in clinical ALD, including cellular mitochondrial damage, elevated cellular reactive oxygen species (ROS) levels, fatty liver, and hepatocyte necrosis. In addition, this model offers potential use in screening drugs for ALD treatment. Overall, the liver organoid model of ALD, which is derived from hiPSC differentiation, has emerged as an invaluable platform for advancing our understanding and management of ALD in clinical settings.
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Affiliation(s)
- Zhiwei Feng
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Bingrui Zhou
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Qizhi Shuai
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Yunliang Wei
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Ning Jin
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Xiaoling Wang
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Hong Zhao
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
| | - Jun Xu
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplant Centerthe First Hospital of Shanxi Medical UniversityTaiyuan030001China
| | - Jianbing Mu
- Laboratory of Malaria and Vector ResearchNational Institute of Allergy and Infectious DiseasesNational Institutes of Health12735 Twinbrook ParkwayUSA
| | - Jun Xie
- Department of Biochemistry and Molecular BiologyShanxi Key Laboratory of Birth Defect and Cell RegenerationMOE Key Laboratory of Coal Environmental Pathogenicity and PreventionShanxi Medical UniversityTaiyuan030001China
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12
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Chang K, Guo R, Hu W, Wang X, Cao F, Qiu J, Li J, Han Q, Du Z, Dou X, Li S. Xie Zhuo Tiao Zhi formula ameliorates chronic alcohol-induced liver injury in mice. Front Pharmacol 2024; 15:1363131. [PMID: 38681193 PMCID: PMC11045942 DOI: 10.3389/fphar.2024.1363131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/03/2024] [Indexed: 05/01/2024] Open
Abstract
This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcohol-activated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IκBα, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease.
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Affiliation(s)
- Kaixin Chang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenbo Hu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xuezhu Wang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Feiwei Cao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiannan Qiu
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiaomei Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiang Han
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhongyan Du
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Zhejiang Engineering Research Center for ‘Preventive Treatment’ Smart Health of Traditional Chinese Medicine, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
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13
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Wu D, Hao O, Hu W, Wu Z, Bian L, Wang H, Zhu J. Circulating cytokines and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study. Scand J Gastroenterol 2024; 59:325-332. [PMID: 37994815 DOI: 10.1080/00365521.2023.2286190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/15/2023] [Accepted: 11/15/2023] [Indexed: 11/24/2023]
Abstract
BACKGROUND Increased inflammation in the liver during ethanol exposure is a major feature of alcoholic liver disease (ALD). An important contributing component to the development of ALD is the inflammatory response brought on by immunological response, however the connection between individual circulating cytokines and ALD is still unclear. To ascertain the causation, we conducted a two-sample bidirectional Mendelian randomization research. METHODS We extracted 41 cytokines and growth factors of 8293 Europeans and ALD cases of the same ethnicity (1416 cases and 217,376 controls) from the Genome-Wide Association Studies (GWAS) database for two-sample bidirectional MR analysis. RESULTS Our analyses suggest that higher interleukin-7 (IL-7) levels are associated with an increased risk of ALD (p = 0.028, OR = 1.191,95% CI = 1.019-1.392), while tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a protective factor for ALD (p = 0.032, OR = 0.863, 95% CI = 0.754-0.988) which can reduce the risk of disease occurrence. In addition, genetically predicted ALD does not affect the expression of circulating cytokines regulators. CONCLUSIONS Our study supports that cytokines play a pivotal role in the pathogenesis of ALD. To determine the mechanisms and pathways of action of these biomarkers, further basic research is required to ensure their clinical suitability for preventing and treating ALD.
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Affiliation(s)
- Duan Wu
- Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ouyang Hao
- Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiye Hu
- Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhaorong Wu
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linke Bian
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongye Wang
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junfeng Zhu
- Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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14
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Yang M, Zhang CY. Interleukins in liver disease treatment. World J Hepatol 2024; 16:140-145. [PMID: 38495285 PMCID: PMC10941743 DOI: 10.4254/wjh.v16.i2.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 02/27/2024] Open
Abstract
Cytokines play pleiotropic roles in human health and disease by regulating both innate and adaptive immune responses. Interleukins (ILs), a large group of cytokines, can be divided into seven families, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, and IL-17 families. Here, we review the functions of ILs in the pathogenesis and resolution of liver diseases, such as liver inflammation (e.g., IL-35), alcohol-related liver disease (e.g., IL-11), non-alcoholic steatohepatitis (e.g., IL-22), liver fibrosis (e.g., Il-17a), and liver cancer (e.g., IL-8). Overall, IL-1 family members are implicated in liver inflammation induced by different etiologies, such as alcohol consumption, high-fat diet, and hepatitis viruses. IL-2 family members mainly regulate T lymphocyte and NK cell proliferation and activation, and the differentiation of T cells. IL-6 family cytokines play important roles in acute phase response in liver infection, liver regeneration, and metabolic regulation, as well as lymphocyte activation. IL-8, also known as CXCL8, is activated in chronic liver diseases, which is associated with the accumulation of neutrophils and macrophages. IL-10 family members contribute key roles to liver immune tolerance and immunosuppression in liver disease. IL-12 family cytokines influence T-cell differentiation and play an essential role in autoimmune liver disease. IL-17 subfamilies contribute to infection defense, liver inflammation, and Th17 cell differentiation. ILs interact with different type I and type II cytokine receptors to regulate intracellular signaling pathways that mediate their functions. However, most clinical studies are only performed to evaluate IL-mediated therapies on alcohol and hepatitis virus infection-induced hepatitis. More pre-clinical and clinical studies are required to evaluate IL-mediated monotherapy and synergistic therapies.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States.
| | - Chun-Ye Zhang
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
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15
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Du X, Jin M, Li R, Zhou F, Sun Y, Mo Q, Song S, Dong N, Duan S, Li M, Lu M, Zhang C, He H, Yang X, Tang C, Li Y. Mechanisms and targeted reversion/prevention of hepatic fibrosis caused by the non-hereditary toxicity of benzo(a)pyrene. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 912:169496. [PMID: 38135085 DOI: 10.1016/j.scitotenv.2023.169496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 11/21/2023] [Accepted: 12/17/2023] [Indexed: 12/24/2023]
Abstract
The effect of long term exposure to low concentrations of environmental pollutants on hepatic disorders is a major public health concern worldwide. Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants. In recent years, an increasing number of studies have focused on the deleterious effects of low concentrations of PAHs in the initiation or exacerbation of the progression of chronic liver disease. However, the underlying molecular mechanisms and effective intervention methods remain unclear. Here, we found that in hepatocytes, a low concentration of benzo(a)pyrene (B[a]P, an indicator of PAHs) chronic exposure continuously activated 14-3-3η via an epigenetic accumulation of DNA demethylation. As a "switch like" factor, 14-3-3η activated its downstream PI3K/Akt signal, which in turn promoted vascular endothelial growth factor (VEGF) production and secretion. As the characteristic fibrogenic paracrine factor regulated by B[a]P/14-3-3η, VEGF significantly induced the neovascularization and activation of hepatic stellate cells, leading to the development of hepatic fibrosis. Importantly, targeted 14-3-3η by using its specific inhibitor invented by our lab could prevent B[a]P-induced hepatic fibrosis, and could even reverse existent hepatic fibrosis caused by B[a]P. The present study not only revealed novel mechanisms, but also proposed an innovative approach for the targeted reversion/prevention of the harmful effects of exposure to PAHs on chronic liver disease.
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Affiliation(s)
- Xinru Du
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ming Jin
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ruzhi Li
- The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fei Zhou
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuanze Sun
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qinliang Mo
- The First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Sisi Song
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Na Dong
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China; The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuoke Duan
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Maoxuan Li
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ming Lu
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chi Zhang
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huiwei He
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Xiaojun Yang
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; Ili & Jiangsu Joint Institute of Health, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Xinjiang, China.
| | - Chengwu Tang
- The First Affiliated Hospital of Huzhou University, Huzhou, China.
| | - Yuan Li
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
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Han Y, Gao H, Gan X, Liu J, Bao C, He C. Roles of IL-11 in the regulation of bone metabolism. Front Endocrinol (Lausanne) 2024; 14:1290130. [PMID: 38352248 PMCID: PMC10862480 DOI: 10.3389/fendo.2023.1290130] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/29/2023] [Indexed: 02/16/2024] Open
Abstract
Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As a member of the IL-6 family, IL-11 acts primarily through the classical signaling pathway IL-11/Receptors, IL-11 (IL-11R)/Glycoprotein 130 (gp130). The regulatory role of IL-11 in bone metabolism has been found earlier, but mainly focuses on the effects on osteogenesis and osteoclasis. In recent years, more studies have focused on IL-11's roles and related mechanisms in different bone metabolism activities. IL-11 regulates osteoblasts, osteoclasts, BM stromal cells, adipose tissue-derived mesenchymal stem cells, and chondrocytes. It's involved in bone homeostasis, including osteogenesis, osteolysis, bone marrow (BM) hematopoiesis, BM adipogenesis, and bone metastasis. This review exams IL-11's role in pathology and bone tissue, the cytokines and pathways that regulate IL-11 expression, and the feedback regulations of these pathways.
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Affiliation(s)
| | | | - Xinling Gan
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | | | | | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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17
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Zhao P, Hou Y, Chen X, Zhang M, Hu Z, Chen L, Huang J. High Fischer Ratio Oligopeptides of Gluten Alleviate Alcohol-Induced Liver Damage by Regulating Lipid Metabolism and Oxidative Stress in Rats. Foods 2024; 13:436. [PMID: 38338571 PMCID: PMC10855637 DOI: 10.3390/foods13030436] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/16/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
High Fischer ratio oligopeptides (HFOs) exhibit diverse biological activities, including anti-inflammatory and antioxidant properties. HFOs from gluten origin were prepared through fermentation and enzymatic hydrolysis and then characterized using free amino acid analysis and scanning electron microscopy (SEM). Following intervention, the levels of serum total cholesterol (TC), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic malondialdehyde (MDA) in the rats significantly decreased (p < 0.05). Simultaneously, there was an increasing trend in superoxide dismutase (SOD) levels, and glutathione (GSH) levels were significantly elevated (p < 0.05). The mRNA expression levels of alcohol metabolism-related genes (ADH4, ALDH2, and CYP2E1) exhibited a significant increase (p < 0.05). Histological examination revealed a reduction in liver damage. The findings indicate that high Fischer ratio oligopeptides, prepared through enzymatic and fermentation methods, significantly improve lipid levels, ameliorate lipid metabolism disorders, and mitigate oxidative stress, and exhibit a discernible alleviating effect on alcoholic liver injury in rats.
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Affiliation(s)
- Penghui Zhao
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Yinchen Hou
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- College of Food and Biological Engineering, Henan University of Animal Husbandry and Economy, Zhengzhou 450044, China
| | - Xinyang Chen
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Mingyi Zhang
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Zheyuan Hu
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
| | - Lishui Chen
- Food Laboratory of Zhong Yuan, Luohe 462300, China
| | - Jihong Huang
- Food Laboratory of Zhong Yuan, Luohe 462300, China
- School of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
- Collaborative Innovation Center of Functional Food Green Manufacturing, Xuchang 461000, China
- State Key Laboratory of Crop Stress Adaptation and Improvement, College of Agriculture, Henan University, Kaifeng 475004, China
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18
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Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J 2023; 480:1987-2008. [PMID: 38054591 PMCID: PMC10754292 DOI: 10.1042/bcj20220160] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/13/2023] [Accepted: 11/27/2023] [Indexed: 12/07/2023]
Abstract
Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.
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Affiliation(s)
- Stuart A. Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
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19
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O’Reilly S. Interleukin-11 and its eminent role in tissue fibrosis: a possible therapeutic target. Clin Exp Immunol 2023; 214:154-161. [PMID: 37724596 PMCID: PMC10714194 DOI: 10.1093/cei/uxad108] [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: 06/27/2023] [Revised: 08/31/2023] [Accepted: 09/15/2023] [Indexed: 09/21/2023] Open
Abstract
Interleukin-11 is a cytokine from the IL-6 family of cytokines that includes IL-6 and oncostatin-M. Initially described for its role in platelet generation, it is now appreciated that this cytokine has multiple functions. Recently it has been found that IL-11 is critical in fibrosis in multiple different organ systems and systemically as in the autoimmune disease systemic sclerosis. Animal models of fibrosis have determined that animals with IL-11 receptor deletions have retarded fibrosis and that in wild-type animals IL-11 is found at the organ of fibrosis. Recent evidence suggests that IL-11 may be a master regulator of fibrosis regardless of end target organ. With the development of neutralizing antibodies targeting the cytokine in pre-clinical models this could be a possible therapeutic, in a disease in which no specific therapies exist. This review appraises the evidence of the role of IL-11 in tissue fibrosis, its signalling properties, and therapeutic targeting. The review ends with an appraisal of indications for which IL-11 modulation is targeted.
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Panahipour L, Abbasabadi AO, Gruber R. Gingival Fibroblasts Are Sensitive to Oral Cell Lysates Indicated by Their IL11 Expression. Bioengineering (Basel) 2023; 10:1193. [PMID: 37892923 PMCID: PMC10604186 DOI: 10.3390/bioengineering10101193] [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: 08/25/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Damaged cells that appear as a consequence of invasive dental procedures or in response to dental materials are supposed to release damage-associated signals. These damage-associated signals not only support tissue regeneration but might also contribute to unwanted fibrosis. The aim of this study was to identify a molecular target that reflects how fibroblasts respond to necrotic oral tissue cells. To simulate the cell damage, we prepared necrotic cell lysates by sonication of the osteocytic cell line IDG-SW3 and exposed them to gingival fibroblasts. RNAseq revealed a moderate increase in IL11 expression in the gingival fibroblasts, a pleiotropic cytokine involved in fibrosis and inflammation, and also in regeneration following trauma. Necrotic lysates of the human squamous carcinoma cell lines HSC2 and TR146, as well as of gingival fibroblasts, however, caused a robust increase in IL11 expression in the gingival fibroblasts. Consistently, immunoassay revealed significantly increased IL11 levels in the gingival fibroblasts when exposed to the respective lysates. Considering that IL11 is a TGF-β target gene, IL11 expression was partially blocked by SB431542, a TGF-β receptor type I kinase inhibitor. Moreover, lysates from the HSC2, TR146, and gingival fibroblasts caused a moderate smad2/3 nuclear translocation in the gingival fibroblasts. Taken together and based on IL11 expression, our findings show that fibroblasts are sensitive to damaged oral tissue cells.
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Affiliation(s)
- Layla Panahipour
- Department of Oral Biology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (L.P.); (A.O.A.)
| | - Azarakhsh Oladzad Abbasabadi
- Department of Oral Biology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (L.P.); (A.O.A.)
| | - Reinhard Gruber
- Department of Oral Biology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (L.P.); (A.O.A.)
- Department of Periodontology, School of Dental Medicine, University of Bern, 3010 Bern, Switzerland
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
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Jiang LF, Yang M, Meng HW, Jia PC, Du CL, Liu JY, Lv XW, Cheng-Huang, Li J. The effect of hepatic stellate cell derived-IL-11 on hepatocyte injury in hepatic fibrosis. Life Sci 2023; 330:121974. [PMID: 37495078 DOI: 10.1016/j.lfs.2023.121974] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 07/28/2023]
Abstract
AIMS This study aimed to elucidate the role of Interleukin-11 (IL-11) in hepatic fibrosis (HF) and its potential as a therapeutic target for HF treatment. MATERIALS AND METHODS We investigated IL-11 expression in patients with varying degrees of liver injury through ELISA and immunohistochemistry. A CCl4-induced HF mouse model was constructed to study IL-11 expression and cell apoptosis using Western blotting (WB) and other techniques. The expression of IL-11 was silenced using rAAV8 in the mouse model. In vitro stimulation of hepatic stellate cells (LX-2) with TGF-β1, and of LO-2 cells with exogenous IL-11, were performed. Cell supernatants of TGF-β1-stimulated LX-2 were used to culture LO-2 cells, with apoptosis monitored via flow cytometry and WB. KEY FINDINGS Increased IL-11 levels were observed in patients and the HF mouse model, with silencing reducing IL-11 expression. In vitro experiments revealed increased endogenous IL-11 in TGF-β1-stimulated LX-2 cells and an increase in apoptotic index, IL11RA, and gp130 in IL-11-stimulated LO-2 cells. Cell apoptosis was reduced in the siRNA/IL11, siRNA/IL11RA, and anti-IL11 groups. WB and immunohistochemistry results showed upregulated p-JNK, p-ERK, and p-P53 expressions in the CCl4-induced HF mouse model and IL-11-treated LO-2 cells. SIGNIFICANCE Our findings suggest IL-11 enhances LX-2 cell activation and proliferation, and promotes LO-2 cell apoptosis through JNK/ERK signaling pathways. This suggests that targeting IL-11 secretion may serve as a potential therapeutic strategy for HF, providing a foundation for its clinical application in HF treatment.
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Affiliation(s)
- Ling-Feng Jiang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Ming Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hong-Wu Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Chang-Lin Du
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jin-Yu Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiong-Wen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Cheng-Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China; Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China.
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22
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Dong J, Lim WW, Shekeran SG, Tan J, Lim SY, Goh JWT, George BL, Schafer S, Cook SA, Widjaja AA. Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury. Int J Mol Sci 2022; 23:ijms23137089. [PMID: 35806094 PMCID: PMC9266364 DOI: 10.3390/ijms23137089] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/04/2022] Open
Abstract
N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1β, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.
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Affiliation(s)
- Jinrui Dong
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Wei-Wen Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore;
| | - Shamini G. Shekeran
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Jessie Tan
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore;
| | - Sze Yun Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Joyce Wei Ting Goh
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Benjamin L. George
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Sebastian Schafer
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
| | - Stuart A. Cook
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169857, Singapore;
- MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK
- Correspondence: (S.A.C.); (A.A.W.)
| | - Anissa A. Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (J.D.); (W.-W.L.); (S.G.S.); (S.Y.L.); (J.W.T.G.); (B.L.G.); (S.S.)
- Correspondence: (S.A.C.); (A.A.W.)
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