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Nam JH, Moon JH, Choi B, Kang GH, Park Y, Park SY, Ko TH, Shin D, Jung Y, Kim SN, Cho YK, Jeon MS. IFN-α and vitamin B6-induced galectin-9 promotes the immunomodulatory function of human clonal mesenchymal stem cells. Stem Cell Res Ther 2025; 16:270. [PMID: 40442825 PMCID: PMC12124064 DOI: 10.1186/s13287-025-04394-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 05/14/2025] [Indexed: 06/02/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) possess a variety of immunomodulatory functions that can vary depending on the MSC line. Investigating priming strategies is essential for increasing the immunomodulatory potential of MSCs. METHODS Human clonal MSCs (cMSCs) were primed with TNF-α, IFN-γ, IL-1β, IFN-α, and vitamin B6. Their immunomodulatory functions, including T-cell proliferation and cytokine production, were analyzed. The primed cMSCs were injected intravenously into a mouse model of ovalbumin-induced atopic dermatitis (AD), and their therapeutic effects were evaluated. RESULTS We identified IFN-α and vitamin B6 as promising priming agents when they are combined with TNF-α and IFN-γ. The primed cMSCs showed expression of galectin-9 (Gal-9), IL-1Ra, and PDL-1. Gal-9 facilitates the induction of regulatory T cells (Tregs) and apoptosis. Treatment with primed cMSCs significantly alleviated pathological changes in an AD mouse model. Notable improvements included a reduction in epidermal thickness (p < 0.05), a decreased number of mast cells and eosinophils in the dermis (p < 0.01), restored expression of claudin-1 in the epidermis (p < 0.0001), and lower serum levels of IgE (p < 0.05). CONCLUSIONS This novel combination of priming factors significantly promotes the immunomodulatory functions of cMSCs by inducing Gal-9. Consequently, Gal-9 may serve as an excellent biomarker for screening primed cMSCs for their immunomodulatory capabilities, facilitating a more accurate assessment of their therapeutic effectiveness.
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Affiliation(s)
- Jee-Hoon Nam
- Department of Molecular Biomedicine, College of Medicine, Inha University, Incheon, Republic of Korea
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Jeong Hyun Moon
- Department of Molecular Biomedicine, College of Medicine, Inha University, Incheon, Republic of Korea
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Byeol Choi
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Geun-Hyung Kang
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Yunok Park
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Se-Yeon Park
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Tae-Hyun Ko
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Donghee Shin
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - YoungSu Jung
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Si-Na Kim
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Yun-Kyoung Cho
- Research Institute, SCM Lifescience, Incheon, Republic of Korea
| | - Myung-Shin Jeon
- Department of Molecular Biomedicine, College of Medicine, Inha University, Incheon, Republic of Korea.
- Research Institute, SCM Lifescience, Incheon, Republic of Korea.
- Translational Research Center, Inha University School of Medicine, Inha University Hospital, B/308 Jungseok Bldg., 366 Seohae-Daero, Jung-Gu, Incheon, 22332, Republic of Korea.
- Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.
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Gangwar A, Saini S, Sharma R. Galectins as Drivers of Host-Pathogen Dynamics in Mycobacterium tuberculosis Infection. ACS Infect Dis 2025. [PMID: 40340374 DOI: 10.1021/acsinfecdis.4c01056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
Galectins form a protein family with a conserved carbohydrate-binding domain that specifically interacts with β-galactoside-containing glycoconjugates, which are found abundantly on mammalian cell surfaces. These proteins play crucial roles in various physiological and pathological processes including immune responses, cell adhesion, inflammation, and apoptosis. During tuberculosis infection, galectins exert diverse impacts on pathogenesis. The interaction between host and pathogen during TB involves intricate mechanisms influencing disease outcomes, where the pathogen exploits host glycosylation patterns to evade immune detection, underscoring the significant role of galectins in regulating these crucial host-pathogen interactions. Galectins facilitate pathogen recognition, enhance the phagocytosis of mycobacteria, support the formation of granuloma, and carefully balance the protective immunity against potential tissue damage. Additionally, galectins have an impact on the cytokine milieu by regulating the levels of pro-inflammatory cytokines and chemokines, essential for orchestrating granuloma formation and maintaining tuberculosis-associated homeostasis. This review delves into the intricate connection between galectins and tuberculosis; uncovering essential molecular mechanisms that deepen our understanding of how these proteins contribute to combating this pervasive infectious disease. Here we discuss the multifaceted roles that galectins play to uniquely and critically influence the core dynamics of host-pathogen interactions in tuberculosis.
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Affiliation(s)
- Anjali Gangwar
- Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sapna Saini
- Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Rashmi Sharma
- Infectious Diseases Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Tung YW, Yang ZS, Huang JY, Hsu YT, Tsui CI, Hemdan MS, Tadikamalla S, Baua AD, Assavalapsakul W, Thitithanyanont A, Chao DY, Liu FT, Wang SF. The Multifaceted Roles of Galectins in Host-Virus Interactions: A Comprehensive Overview. Glycobiology 2025; 35:cwaf026. [PMID: 40302013 DOI: 10.1093/glycob/cwaf026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/25/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025] Open
Abstract
Galectins are a family of β-galactosides-binding protein, crucial regulators of host-virus interactions. They achieve this by recognizing specific glycan patterns on viral surfaces or mediating interactions with intracellular viral or host proteins, subsequently influencing the critical phases of the viral life cycle, such as attachment, replication, immune evasion, and reactivation. Furthermore, galectins modulate host immune responses, shaping the progression and outcomes of viral infections. This review comprehensively examines the roles of both endogenous and exogenous galectins in viral infections, noting that only a few galectins, including Galectin-1, -3, -4, -7, -8, and -9, Have been identified as key players in viral infection. Notably, Galectin-1, -3, and -9 play diverse functions in both DNA and RNA viral infection. Emerging evidence highlights the potential of Galectin-4 and -8 as intracellular sensors and modulators of viral pathogenesis. Endogenous galectins, produced by host cells, act through both glycan-dependent and glycan-independent mechanisms, influencing viral processes and immune responses. Exogenous galectins, which are secreted by other cells or administered as recombinant proteins, can either enhance or counteract the actions of endogenous galectins. The functions of galectins are virus-specific and context-dependent, serving as either promoters or inhibitors of viral replication and reactivation. Dysregulation of galectin expression is often linked to disease progression, highlighting their potential as diagnostic and prognostic biomarkers, as well as therapeutic targets. The important and varied roles that galectins play in viral infections are highlighted in this review, which also provides fresh insights into host-pathogen interactions and the development of antiviral tactics. HIGHLIGHTS
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Affiliation(s)
- Ying-Wei Tung
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Zih-Syuan Yang
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Jie-Yu Huang
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Yun-Tzu Hsu
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Ching-I Tsui
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Mahmoud Salama Hemdan
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Sneha Tadikamalla
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
| | - Albright Dew Baua
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 807, Taiwan
| | - Wanchai Assavalapsakul
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Phayathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Arunee Thitithanyanont
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama VI Road, Ratchathewi, Bangkok 10400, Thailand
| | - Day-Yu Chao
- Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung 40227, Taiwan
| | - Fu-Tong Liu
- Department of Dermatology, Keck School of Medicine of USC, 1975 Zonal Ave, Los Angeles, CA 90033, United States
- Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Nankang, Taipei 11529, Taiwan
| | - Sheng-Fan Wang
- Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- M.Sc. Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung 80756, Taiwan
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Ling J, You S, Chen W, Yang X, Xv Y, Zhu B. Galectin-9 as a new biomarker of acute-on-chronic liver failure. Sci Rep 2024; 14:22303. [PMID: 39333198 PMCID: PMC11437140 DOI: 10.1038/s41598-024-73397-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 09/17/2024] [Indexed: 09/29/2024] Open
Abstract
Galectin-9 (Gal-9) expression in patients with acute-on-chronic liver failure and its correlation with prognosis remain unclear. This study investigated the relationship between liver failure prognosis and Gal-9 expression analysis in patients with acute-on-chronic liver failure. Patients with acute-on-chronic liver failure attributable to hepatitis B and those with chronic hepatitis B were included in this single-center prospective cohort study. The Gal-9 levels in the acute-on-chronic liver failure group were significantly higher than those in the chronic hepatitis B group, and there was an upregulation of Gal-9 and T-cell immunoglobulin domain and mucin domain-3 expressions in peripheral blood T cells. Gal-9 was localized in the regenerative areas of liver tissues in patients with acute-on-chronic liver failure, co-localizing with Kupffer cells. Kaplan-Meier survival curves showed that patients with Gal-9 levels < 9.6 ng/ml had a worse prognosis, with the area under the receiver operating characteristic curve (AUC-ROC) being similar to that of the Model for End-Stage Liver Disease score. The combined ROC curve of the two had better predictive performance, with an AUC of 0.945. High Gal-9 levels in liver regenerative areas can serve as a prognostic marker, indicating a better prognosis for patients with hepatitis B virus-acute-on-chronic liver failure.
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Affiliation(s)
- Jun Ling
- Hepatology Department, The Fifth Medical Center of Chinese PLA General Hospital, No. 100, Xisi Huanzhong Road, Beijing, 10039, China
| | - Shaoli You
- Hepatology Department, The Fifth Medical Center of Chinese PLA General Hospital, No. 100, Xisi Huanzhong Road, Beijing, 10039, China
| | - Weiwei Chen
- Infectious Disease Department, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 10039, China
| | - Xinxin Yang
- Infectious Disease Department, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 10039, China
| | - Yiwen Xv
- Hepatology Department, The Fifth Medical Center of Chinese PLA General Hospital, No. 100, Xisi Huanzhong Road, Beijing, 10039, China
| | - Bing Zhu
- Hepatology Department, The Fifth Medical Center of Chinese PLA General Hospital, No. 100, Xisi Huanzhong Road, Beijing, 10039, China.
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Elahi S, Rezaeifar M, Osman M, Shahbaz S. Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function. Front Immunol 2024; 15:1443363. [PMID: 39386210 PMCID: PMC11461188 DOI: 10.3389/fimmu.2024.1443363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 09/03/2024] [Indexed: 10/12/2024] Open
Abstract
This study aimed to assess plasma galectin-9 (Gal-9) and artemin (ARTN) concentrations as potential biomarkers to differentiate individuals with Long COVID (LC) patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from SARS-CoV-2 recovered (R) and healthy controls (HCs). Receiver operating characteristic (ROC) curve analysis determined a cut-off value of plasma Gal-9 and ARTN to differentiate LC patients from the R group and HCs in two independent cohorts. Positive correlations were observed between elevated plasma Gal-9 levels and inflammatory markers (e.g. SAA and IP-10), as well as sCD14 and I-FABP in LC patients. Gal-9 also exhibited a positive correlation with cognitive failure scores, suggesting its potential role in cognitive impairment in LC patients with ME/CFS. This study highlights plasma Gal-9 and/or ARTN as sensitive screening biomarkers for discriminating LC patients from controls. Notably, the elevation of LPS-binding protein in LC patients, as has been observed in HIV infected individuals, suggests microbial translocation. However, despite elevated Gal-9, we found a significant decline in ARTN levels in the plasma of people living with HIV (PLWH). Our study provides a novel and important role for Gal-9/ARTN in LC pathogenesis.
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Affiliation(s)
- Shokrollah Elahi
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, Edmonton, AB, Canada
- Women and Children Health Research Institute, Edmonton, AB, Canada
- Cancer Research Institute of Northern Alberta, Edmonton, AB, Canada
- Glycomics Institute of Alberta, Edmonton, AB, Canada
- Alberta Transplant Institute, Edmonton, AB, Canada
| | - Maryam Rezaeifar
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
| | - Mohammed Osman
- Li Ka Shing Institute of Virology, Edmonton, AB, Canada
- Women and Children Health Research Institute, Edmonton, AB, Canada
- Department of Medicine, Division of Rheumatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Shima Shahbaz
- School of Dentistry, Division of Foundational Sciences, Edmonton, AB, Canada
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Song J, Zheng J, Li Z, Fu L, Yang J, Li K, Yu X, Lv B, Du J, Huang Y, Jin H. Sulfur dioxide inhibits mast cell degranulation by sulphenylation of galectin-9 at cysteine 74. Front Immunol 2024; 15:1369326. [PMID: 38953022 PMCID: PMC11215078 DOI: 10.3389/fimmu.2024.1369326] [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: 01/12/2024] [Accepted: 05/24/2024] [Indexed: 07/03/2024] Open
Abstract
Objectives Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation. Methods HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC β-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation. Results Degranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions. Conclusion These findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.
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Affiliation(s)
- Jiaru Song
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Jie Zheng
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Zongmin Li
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Ling Fu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Jing Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Science Beijing, Beijing Institute of Lifeomics, Beijing, China
| | - Kun Li
- Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China
| | - Xiaoqi Yu
- Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China
| | - Boyang Lv
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Peking University First Hospital, Beijing, China
| | - Yaqian Huang
- Department of Pediatrics, Peking University First Hospital, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Peking University First Hospital, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
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Zhu Q, Yang Y, Chen K, Zhang Q, Huang Y, Jian S. Diffuse large B-cell lymphoma: the significance of CD8 + tumor-infiltrating lymphocytes exhaustion mediated by TIM3/Galectin-9 pathway. J Transl Med 2024; 22:174. [PMID: 38369502 PMCID: PMC10874540 DOI: 10.1186/s12967-024-05002-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Overexpression of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is related to the exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) in diffuse large B-cell lymphoma (DLBCL). However, the mechanism of TIM3-mediated CD8+TILs exhaustion in DLBCL remains poorly understood. Therefore, we aimed to clarify the potential pathway involved in TIM3-mediated CD8+TILs exhaustion and its significance in DLBCL. METHODS The expression of TIM3 and its correlation with CD8+TILs exhaustion, the key ligand of TIM3, and the potential pathway of TIM3-mediated CD8+TILs exhaustion in DLBCL were analyzed using single-cell RNA sequencing and validated by RNA sequencing. The biological significance of TIM3-related pathway in DLBCL was investigated based on RNA sequencing, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction data. Finally, the possible regulatory mechanism of TIM3-related pathway in DLBCL was explored using single-cell RNA sequencing and RNA sequencing. RESULTS Our results demonstrated that CD8+TILs, especially the terminally exhausted state, were the major clusters that expressed TIM3 in DLBCL. Galectin-9, mainly expressed in M2 macrophages, is the key ligand of TIM3 and can induce the exhaustion of CD8+TILs through TIM3/Galectin-9 pathway. Meanwhile, high TIM3/Galectin-9 enrichment is related to immunosuppressive tumor microenvironment, severe clinical manifestations, inferior prognosis, and poor response to CHOP-based chemotherapy, and can predict the clinical efficacy of immune checkpoint blockade therapy in DLBCL. Furthermore, the TIM3/Galectin-9 enrichment in DLBCL may be regulated by the IFN-γ signaling pathway. CONCLUSIONS Our study highlights that TIM3/Galectin-9 pathway plays a crucial role in CD8+TILs exhaustion and the immune escape of DLBCL, which facilitates further functional studies and could provide a theoretical basis for the development of novel immunotherapy in DLBCL.
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Affiliation(s)
- Qiqi Zhu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China
| | - Yiming Yang
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China
| | - Kexin Chen
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China
| | - Qiaoyu Zhang
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China
| | - Yifan Huang
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China
| | - Shunhai Jian
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China.
- Department of Pathology, North Sichuan Medical College, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan Nan Road, Nanchong, 637000, Sichuan, China.
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Chen PK, Hsu WF, Peng CY, Liao TL, Chang SH, Chen HH, Chen CH, Chen DY. Significant association of elevated serum galectin-9 levels with the development of non-alcoholic fatty liver disease in patients with rheumatoid arthritis. Front Med (Lausanne) 2024; 11:1347268. [PMID: 38371515 PMCID: PMC10869587 DOI: 10.3389/fmed.2024.1347268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/22/2024] [Indexed: 02/20/2024] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is prevalent among rheumatoid arthritis (RA) patients, but its pathogenesis has rarely been explored. Galectin-9 (Gal-9) interacts with T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3) expressed on hepatocytes and thus regulates T cell proliferation in a murine model of NAFLD. We aimed to examine the pathogenic role of the Gal-9/TIM-3 pathway in RA-NAFLD. Methods Serum levels of Gal-9, soluble TIM-3 (sTIM-3), fatty acid-binding proteins (FABP)1, and FABP4 were determined by ELISA in forty-five RA patients and eleven healthy participants. Using Oil-red O staining and immunoblotting, we examined the effects of Gal-9 and free fatty acid (FFA) on lipid accumulation in human hepatocytes and FABP1 expression. Results Serum Gal-9, sTIM-3 and FABP1 level were significantly higher in RA patients (median 5.02 ng/mL, 3.42 ng/mL, and 5.76 ng/mL, respectively) than in healthy participants (1.86 ng/mL, 0.99 ng/mL, and 0.129 ng/mL, all p < 0.001). They were also significantly higher in patients with moderate-to-severe NAFLD compared with none-to-mild NAFLD (p < 0.01; p < 0.05; and p < 0.01, respectively). Serum Gal-9 levels were positively correlated with sTIM-3, FABP1, FABP4 levels, and ultrasound-fatty liver score, respectively, in RA patients. Multivariate regression analysis revealed that Gal-9 (cut-off>3.30) was a significant predictor of NAFLD development, and Gal-9 and sTIM-3 were predictors of NAFLD severity (both p < 0.05). The cell-based assay showed that Gal-9 and FFA could upregulate FABP1 expression and enhance lipid droplet accumulation in hepatocytes. Conclusion Elevated levels of Gal-9 and sTIM3 in RA patients with NAFLD and their positive correlation with NAFLD severity suggest the pathogenic role of Gal-9 signaling in RA-related NAFLD.
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Affiliation(s)
- Po-Ku Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- Translational Medicine Laboratory, China Medical University Hospital, Taichung, Taiwan
| | - Wei-Fan Hsu
- College of Medicine, China Medical University, Taichung, Taiwan
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- College of Medicine, China Medical University, Taichung, Taiwan
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tsai-Ling Liao
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- College of Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Shih-Hsin Chang
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Hsin-Hua Chen
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Division of General Medicine, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chu-Huang Chen
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, United States
- Institute for Biomedical Sciences, Shinshu University, Nagano, Japan
| | - Der-Yuan Chen
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- Translational Medicine Laboratory, China Medical University Hospital, Taichung, Taiwan
- College of Medicine, China Medical University, Taichung, Taiwan
- Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- College of Medicine, National Chung Hsing University, Taichung, Taiwan
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9
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Karamese M, Gumus A, Atalay E, Tutuncu EE. Assessment of the levels of some prognostic biomolecules (galectins, ACE2, SCUBE1/2/3) in COVID-19 patients. Future Microbiol 2023; 18:1329-1337. [PMID: 37910069 DOI: 10.2217/fmb-2023-0099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/20/2023] [Indexed: 11/03/2023] Open
Abstract
Aim: Our aim was to investigate the differences between healthy people and COVID-19 patients in terms of some immunological biomolecules, especially including those related to the inflammation process. Materials & methods: A total of 180 participants (90 healthy controls and 90 COVID-19 patients) were included. The expression levels of eight different inflammation-related biomolecules were measured by the ELISA technique. Results: The mean levels of ACE2, ANG1-7, GAL3, GAL9, SCUBE1, SCUBE2 and SCUBE3 were elevated in COVID-19 patients when compared with healthy controls, while the mean level of GAL2 was lower in COVID-19 patients than controls. Conclusion: To understand the cytokine storm mechanism and related parameters, more detailed studies should be performed investigating more related biomolecules and related signaling pathways.
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Affiliation(s)
- Murat Karamese
- Department of Medical Microbiology, Kafkas University, Faculty of Medicine, Kars, 36100, Turkey
| | - Abdullah Gumus
- Department of Medical Microbiology, Kafkas University, Faculty of Medicine, Kars, 36100, Turkey
| | - Eray Atalay
- Department of Internal Medicine, Kafkas University, Faculty of Medicine, Kars, 36100, Turkey
| | - Emin E Tutuncu
- Department of Clinical Microbiology & Infectious Diseases, Etlik City Hospital, Ankara, 06100, Turkey
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10
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Cogliati B, Yashaswini CN, Wang S, Sia D, Friedman SL. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol 2023; 20:647-661. [PMID: 37550577 PMCID: PMC10671228 DOI: 10.1038/s41575-023-00821-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2023] [Indexed: 08/09/2023]
Abstract
Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.
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Affiliation(s)
- Bruno Cogliati
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
| | | | - Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniela Sia
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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11
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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12
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Jiang D, Ma X, Zhang X, Cheng B, Wang R, Liu Y, Zhang X. New techniques: a roadmap for the development of HCC immunotherapy. Front Immunol 2023; 14:1121162. [PMID: 37426674 PMCID: PMC10323423 DOI: 10.3389/fimmu.2023.1121162] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 06/09/2023] [Indexed: 07/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The absence of effective early diagnostic methods and the limitations of conventional therapies have led to a growing interest in immunotherapy as a novel treatment approach for HCC. The liver serves as an immune organ and a recipient of antigens from the digestive tract, creating a distinctive immune microenvironment. Key immune cells, including Kupffer cells and cytotoxic T lymphocytes, play a crucial role in HCC development, thus offering ample research opportunities for HCC immunotherapy. The emergence of advanced technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and single-cell ribonucleic acid sequencing has introduced new biomarkers and therapeutic targets, facilitating early diagnosis and treatment of HCC. These advancements have not only propelled the progress of HCC immunotherapy based on existing studies but have also generated new ideas for clinical research on HCC therapy. Furthermore, this review analysed and summarised the combination of current therapies for HCC and the improvement of CRISPR technology for chimeric antigen receptor T cell therapy, instilling renewed hope for HCC treatment. This review comprehensively explores the advancements in immunotherapy for HCC, focusing on the use of new techniques.
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13
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Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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14
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Tsai MT, Yang RB, Ou SM, Tseng WC, Lee KH, Yang CY, Chang FP, Tarng DC. Plasma Galectin-9 Is a Useful Biomarker for Predicting Renal Function in Patients Undergoing Native Kidney Biopsy. Arch Pathol Lab Med 2023; 147:167-176. [PMID: 35687787 DOI: 10.5858/arpa.2021-0466-oa] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2021] [Indexed: 02/05/2023]
Abstract
CONTEXT.— Galectin-9 reduces tissue damage in certain immune-mediated glomerular diseases. However, its role in structural and functional renal changes in patients with varying types of chronic kidney disease (CKD) is less clear. OBJECTIVE.— To investigate the association between plasma galectin-9 levels, proteinuria, tubulointerstitial lesions, and renal function in different CKD stages. DESIGN.— We measured plasma galectin-9 levels in 243 patients undergoing renal biopsy for determining the CKD etiology. mRNA and protein expression levels of intrarenal galectin-9 were assessed by quantitative real-time polymerase chain reaction and immunostaining. Relationships between plasma galectin-9, clinical characteristics, and tubulointerstitial damage were analyzed with logistic regression. We investigated galectin-9 expression patterns in vitro in murine J774 macrophages treated with differing stimuli. RESULTS.— To analyze the relationship between galectin-9 and clinical features, we divided the patients into 2 groups according to median plasma galectin-9 levels. The high galectin-9 group tended to be older and to have decreased renal function, higher proteinuria, and greater interstitial fibrosis. After multivariable adjustment, elevated plasma galectin-9 levels were independently associated with stage 3b or higher CKD. An analysis of gene expression in the tubulointerstitial compartment in the biopsy samples showed a significant positive correlation between intrarenal galectin-9 mRNA expression and plasma galectin-9 levels. Immunohistochemistry confirmed increased galectin-9 expression in the renal interstitium of patients with advanced CKD, and most galectin-9-positive cells were macrophages, as determined by double-immunofluorescence staining. In vitro experiments showed that galectin-9 expression in macrophages was significantly increased after interferon-γ stimulation. CONCLUSIONS.— Our findings suggest that plasma galectin-9 is a good biomarker for diagnosing advanced CKD.
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Affiliation(s)
- Ming-Tsun Tsai
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan.,Tsai and R-B Yang contributed equally to this manuscript
| | - Ruey-Bing Yang
- From the Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (R-B Yang).,Tsai and R-B Yang contributed equally to this manuscript
| | - Shuo-Ming Ou
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Cheng Tseng
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kuo-Hua Lee
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Yu Yang
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Fu-Pang Chang
- From the Department of Pathology and Laboratory Medicine (Chang), Taipei Veterans General Hospital, Taipei, Taiwan
| | - Der-Cherng Tarng
- From the Division of Nephrology, Department of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), Taipei Veterans General Hospital, Taipei, Taiwan.,From the Institute of Clinical Medicine, School of Medicine (Tsai, Ou, Tseng, Lee, C-Y Yang, Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan.,From the Department and Institute of Physiology (Tarng), National Yang Ming Chiao Tung University, Taipei, Taiwan
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15
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Combined Immune Checkpoint Blockade Enhances Antiviral Immunity against Bovine Leukemia Virus. J Virol 2023; 97:e0143022. [PMID: 36598199 PMCID: PMC9888214 DOI: 10.1128/jvi.01430-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Bovine leukemia virus (BLV) is a retrovirus that causes enzootic bovine leukosis (EBL) in cattle and is widespread in many countries, including Japan. Recent studies have revealed that the expression of immunoinhibitory molecules, such as programmed death-1 (PD-1) and PD-ligand 1, plays a critical role in immunosuppression and disease progression during BLV infection. In addition, a preliminary study has suggested that another immunoinhibitory molecule, T-cell immunoglobulin domain and mucin domain-3 (TIM-3), is involved in immunosuppression during BLV infection. Therefore, this study was designed to further elucidate the immunoinhibitory role of immune checkpoint molecules in BLV infection. TIM-3 expression was upregulated on peripheral CD4+ and CD8+ T cells in BLV-infected cattle. Interestingly, in EBL cattle, CD4+ and CD8+ T cells infiltrating lymphomas expressed TIM-3. TIM-3 and PD-1 were upregulated and coexpressed in peripheral CD4+ and CD8+ T cells from BLV-infected cattle. Blockade by anti-bovine TIM-3 monoclonal antibody increased CD69 expression on T cells and gamma interferon (IFN-γ) production from peripheral blood mononuclear cells from BLV-infected cattle. A syncytium formation assay also demonstrated the antiviral effects of TIM-3 blockade against BLV infection. The combined inhibition of TIM-3 and PD-1 pathways significantly enhanced IFN-γ production and antiviral efficacy compared to inhibition alone. In conclusion, the combined blockade of TIM-3 and PD-1 pathways shows strong immune activation and antiviral effects and has potential as a novel therapeutic method for BLV infection. IMPORTANCE Enzootic bovine leukosis caused by bovine leukemia virus (BLV) is an important viral disease in cattle, causing severe economic losses to the cattle industry worldwide. The molecular mechanisms of BLV-host interactions are complex. Previously, it was found that immune checkpoint molecules, such as PD-1, suppress BLV-specific Th1 responses as the disease progresses. To date, most studies have focused only on how PD-1 facilitates escape from host immunity in BLV-infected cattle and the antiviral effects of the PD-1 blockade. In contrast, how T-cell immunoglobulin domain and mucin domain-3 (TIM-3), another immune checkpoint molecule, regulates anti-BLV immune responses is rarely reported. It is also unclear why PD-1 inhibition alone was insufficient to exert anti-BLV effects in previous clinical studies. In this study, the expression profile of TIM-3 in T cells derived from BLV-infected cattle suggested that TIM-3 upregulation is a cause of immunosuppression in infected cattle. Based on these results, anti-TIM-3 antibody was used to experimentally evaluate its function in influencing immunity against BLV. Results indicated that TIM-3 upregulation induced by BLV infection suppressed T-cell activation and antiviral cytokine production. Some T cells coexpressed PD-1 and TIM-3, indicating that simultaneous inhibition of PD-1 and TIM-3 with their respective antibodies synergistically restored antiviral immunity. This study could open new avenues for treating bovine chronic infections.
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16
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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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17
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HEIDARI FATEMEH, SEYEDEBRAHIMI REIHANEH, YANG PIAO, FARSANI MOHSENESLAMI, ABABZADEH SHIMA, KALHOR NASER, MANOOCHEHRI HAMED, SHEYKHHASAN MOHSEN, AZIMZADEH MARYAM. Exosomes in viral infection: Effects for pathogenesis and treatment strategies. BIOCELL 2023; 47:2597-2608. [DOI: 10.32604/biocell.2023.043351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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18
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Yin Y, Zhao Y, Chen Q, Chen Y, Mao L. Dual roles and potential applications of exosomes in HCV infections. Front Microbiol 2022; 13:1044832. [PMID: 36578571 PMCID: PMC9791051 DOI: 10.3389/fmicb.2022.1044832] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/22/2022] [Indexed: 12/14/2022] Open
Abstract
The hepatitis C virus (HCV) causes severe liver diseases, including hepatitis, liver cirrhosis, and hepatocellular carcinoma, which have high morbidity and mortality. Antibody targeting receptor-mediated HCV infections have limited therapeutic benefits, suggesting that the transmission of HCV infections is possibly mediated via receptor-independent mechanisms. Exosomes are membrane-enclosed vesicles with a diameter of 30-200 nm, which originate from the fusion of endosomal multivesicular bodies with the plasma membrane. Accumulating evidence suggests that exosomes have a pivotal role in HCV infections. Exosomes can transfer viral and cellular bioactive substances, including nucleic acids and proteins, to uninfected cells, thus spreading the infection by masking these materials from immunological recognition. In addition, exosomes originating from some cells can deliver antiviral molecules or prompt the immune response to inhibit HCV infection. Exosomes can be used for the diagnosis of HCV-related diseases, and are being presently evaluated as therapeutic tools for anti-HCV drug delivery. This review summarizes the current knowledge on the dual roles and potential clinical applications of exosomes in HCV infections.
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19
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Liu S, Xu C, Yang F, Zong L, Qin Y, Gao Y, Su Q, Li T, Li Y, Xu Y, Zheng M. Natural Killer Cells Induce CD8+ T Cell Dysfunction via Galectin-9/TIM-3 in Chronic Hepatitis B Virus Infection. Front Immunol 2022; 13:884290. [PMID: 35874664 PMCID: PMC9301626 DOI: 10.3389/fimmu.2022.884290] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 05/20/2022] [Indexed: 11/30/2022] Open
Abstract
The antiviral response of natural killer (NK) cells and CD8+ T cells is weak in patients with chronic hepatitis B (CHB) infection. However, the specific characteristics of these cells and the association between NK cells and CD8+ T cell dysfunction is not well known. In this study, higher galectin-9 (Gal-9) expression was observed in circulating NK cells from CHB patients than from healthy controls and was found to contribute to NK cell dysfunction. In addition, circulating CD8+ T cells showed obvious dysfunction and overexpressed TIM-3, the natural receptor of Gal-9, during active CHB infection. Gal-9+ and Gal-9- NK cells from active CHB patients were sorted and cocultured with autologous CD8+ T cells. The proportion of tetramer+CD8+ T cells and the cytokines production of CD8+ T cells were lower after cocultivation with Gal-9+ than with Gal-9- NK cells. We showed that in vitro depletion of NK cells increased circulating hepatitis B virus (HBV)-specific CD8+ T cell responses in patients with active CHB infection. Because Gal-9 is increased in the serum of CHB patients, CD8+ T cells were sorted and cultured with exogenous Gal-9, resulting in lower IFN-γ, TNF-α, CD107a, and granzyme B levels, decreased expression of the activation receptor CD69, increased expression of TIM-3, and a high percentage of early apoptotic CD8+ T cells. Blocking Gal-9 or TIM-3 in vitro in a culture of peripheral blood mononuclear cells (PBMCs) stimulated with HBV peptide from active CHB patients restored CD8+ T cell function. However, blocking Gal-9 in vitro after removal of NK cells from PBMCs did not rescue CD8+ T cells exhaustion. Furthermore, NK and CD8+ T cells from active CHB patients were sorted and cocultured in vitro, and the exhaustion of CD8+ T cells were alleviated after blocking Gal-9 or TIM-3. In summary, overexpression of Gal-9 on NK cells, which interacts with TIM-3+CD8+ T cells and likely contributes to antiviral CD8+ T cell dysfunction, may be a potential target for the treatment of CHB patients.
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Affiliation(s)
- Siyu Liu
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang Xu
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fan Yang
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lu Zong
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yizu Qin
- Anhui Center for Disease Control and Prevention, Hefei, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qian Su
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tuantuan Li
- Department of Clinical Laboratory, Second People’s Hospital of Fuyang City, Fuyang, China
| | - Ye Li
- The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yuanhong Xu
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: *Meijuan Zheng,
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20
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Hai Nam N, Taura K, Koyama Y, Nishio T, Yamamoto G, Uemoto Y, Kimura Y, Xuefeng L, Nakamura D, Yoshino K, Ogawa E, Okamoto T, Yoshizawa A, Seo S, Iwaisako K, Yoh T, Hata K, Masui T, Okajima H, Haga H, Uemoto S, Hatano E. Increased Expressions of Programmed Death Ligand 1 and Galectin 9 in Transplant Recipients Who Achieved Tolerance After Immunosuppression Withdrawal. Liver Transpl 2022; 28:647-658. [PMID: 34655506 DOI: 10.1002/lt.26336] [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: 08/21/2021] [Revised: 09/27/2021] [Accepted: 10/06/2021] [Indexed: 01/13/2023]
Abstract
Programmed death 1 (PD1)/its ligand PD-L1 concomitant with T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)/its ligand galectin 9 (Gal-9) and the forkhead box P3 (FOXP3) might be involved in tolerance after liver transplantation (LT). Liver biopsies from 38 tolerant, 19 nontolerant (including 16 samples that triggered reintroduction of immunosuppression [IS] and 19 samples after IS reintroduction), and 38 control LT patients were studied. The expressions of PD1, PD-L1, Gal-9, and FOXP3 were determined by immunohistochemical and immunofluorescence (IF) staining. The success period of IS withdrawal was calculated using Kaplan-Meier curve analysis. Tolerant and control patients exhibited higher PD-L1, Gal-9, and FOXP3 levels than nontolerant patients at the moment of triggering IS reintroduction. High expressions of PD-L1 and Gal-9 were associated with prolonged success of tolerance (83.3% versus 36.7% [P < 0.01] and 73.1% versus 42.9% [P = 0.03]). A strong correlation between PD-L1 and Gal-9 expression levels was detected (Spearman r = 0.73; P ≤ 0.001), and IF demonstrated colocalization of PD-L1 and Gal-9 in the cytoplasm of hepatocytes. In conclusion, the present study demonstrated that increased expressions of PD-L1 and Gal-9 were associated with sustained tolerance after IS withdrawal in pediatric liver transplantation.
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Affiliation(s)
- Nguyen Hai Nam
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Nishio
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Gen Yamamoto
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Uemoto
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Kimura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Li Xuefeng
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daichi Nakamura
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kenji Yoshino
- Department of Surgery, Nagahama City Hospital, Nagahama, Japan
| | - Eri Ogawa
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | - Tatsuya Okamoto
- Department of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan
| | | | - Satoru Seo
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Tomoaki Yoh
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshihiko Masui
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideaki Okajima
- Department of Pediatric Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Hironori Haga
- Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan
| | | | - Etsuro Hatano
- Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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21
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Kuske M, Haist M, Jung T, Grabbe S, Bros M. Immunomodulatory Properties of Immune Checkpoint Inhibitors-More than Boosting T-Cell Responses? Cancers (Basel) 2022; 14:1710. [PMID: 35406483 PMCID: PMC8996886 DOI: 10.3390/cancers14071710] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022] Open
Abstract
The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40-60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.
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Affiliation(s)
| | | | | | | | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.K.); (M.H.); (T.J.); (S.G.)
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22
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Wu Y, Huang S, Xiao S, He J, Lu F. Impact of Galectin-Receptor Interactions on Liver Pathology During the Erythrocytic Stage of Plasmodium berghei Malaria. Front Immunol 2021; 12:758052. [PMID: 34899708 PMCID: PMC8652201 DOI: 10.3389/fimmu.2021.758052] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/05/2021] [Indexed: 12/25/2022] Open
Abstract
Hepatopathy is frequently observed in patients with severe malaria but its pathogenesis remains unclear. Galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses, and exhibit pivotal roles during Plasmodium spp. infection. Here, we analyzed the impact of blockage of galectin-receptor interactions by treatment with alpha (α)-lactose on liver immunopathology during the erythrocytic stage of malaria in mice infected with Plasmodium berghei ANKA (PbANKA). Our results found that compared with PbANKA-infected mice (malarial mice), blockage of galectin-receptor interactions led to decreased host survival rate and increased peripheral blood parasitemia; exacerbated liver pathology, increased numbers of CD68+ macrophages and apoptotic cells, and increased parasite burden in the livers on days 5 and 7 post infection (p.i.) as well as increased mRNA expression levels of galectin-9 (Gal-9) and its receptor, the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), interferon (IFN)α, IFNγ, and the triggering receptor expressed on myeloid cells (TREM)-1 in the livers or spleens of PbANKA-infected mice on day 7 p.i. Observed by transmission electron microscopy, the peritoneal macrophages isolated from malarial mice with α-lactose treatment had more pseudopodia than those from malarial mice. Measured by using quantitative real-time reverse transcription-polymerase chain reaction assay, the mRNA expression levels of Gal-9, IFNα, IFNβ, IFNγ, and TREM-1 were increased in the peritoneal macrophages isolated from malarial mice with α-lactose treatment in comparison of those from malarial mice. Furthermore, significant positive correlations existed between the mRNA levels of Gal-9 and Tim-3/IFNγ/TREM-1 in both the livers and the peritoneal macrophages, and between Gal-9 and Tim-3/TREM-1 in the spleens of malarial mice; significant positive correlations existed between the mRNA levels of Gal-9 and IFNγ in the livers and between Gal-9 and IFNα in the peritoneal macrophages from malarial mice treated with α-lactose. Our data suggest a potential role of galectin-receptor interactions in limiting liver inflammatory response and parasite proliferation by down-regulating the expressions of IFNα, IFNγ, and TREM-1 during PbANKA infection.
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Affiliation(s)
- Yifan Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shiguang Huang
- School of Stomatology, Jinan University, Guangzhou, China
| | - Siyu Xiao
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jian He
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Public Experimental Teaching Center, Sun Yat-sen University, Guangzhou, China
| | - Fangli Lu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Clinical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China
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23
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Bao Y, Jiang A, Dong K, Gan X, Gong W, Wu Z, Liu B, Bao Y, Wang J, Wang L. DDX39 as a predictor of clinical prognosis and immune checkpoint therapy efficacy in patients with clear cell renal cell carcinoma. Int J Biol Sci 2021; 17:3158-3172. [PMID: 34421357 PMCID: PMC8375229 DOI: 10.7150/ijbs.62553] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/06/2021] [Indexed: 01/12/2023] Open
Abstract
DEAD-box protein 39 (DDX39) has been demonstrated to be a tumorigenic gene in multiple tumor types, but its role in the progression and immune microenvironment of clear cell renal cell cancer (ccRCC) remains unclear. The aim of the present study was to investigate the role of DDX39 in the ccRCC tumor progression, immune microenvironment and efficacy of immune checkpoint therapy. The DDX39 expression level was first detected in tumors in the public data and then verified in ccRCC samples from Changzheng Hospital. The prognostic value of DDX39 expression was assessed in the Cancer Genome Atlas (TCGA) and ccRCC patients from Changhai Hospital. The role of DDX39 in promoting ccRCC was analyzed by bioinformatic analysis and in vitro experiments. The association between DDX39 expression and immune cell infiltration and immune inhibitory markers was analyzed, and its value in predicting the immune checkpoint therapy efficacy in ccRCC were evaluated in the public database. DDX39 expression was elevated in Oncomine, GEO and TCGA ccRCC databases, as well as in Changzheng ccRCC samples. In TCGA ccRCC patients, increased DDX39 expression predicted worse overall survival (OS) (p<0.0001) and progression-free interval (PFI) (p<0.0001), and was shown as an independent predictive factor for OS (p=0.002). These findings were consistent with those from Changhai ccRCC patients. In addition, GO and GSEA analysis identified DDX39 as a pro-ccRCC gene. In vitro experiments confirmed the role of DDX39 in promoting ccRCC cell. Finally, DDX39 was found to be positively correlated with a variety of immune inhibitory markers, and could predict the adverse efficacy of immune checkpoint therapy in TIDE analysis. In conclusion, Increased DDX39 in ccRCC patients predicted worse clinical prognosis, promoted ccRCC cell proliferation, migration and invasion, and also predicted adverse efficacy of immune checkpoint therapy.
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Affiliation(s)
- Yewei Bao
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Kai Dong
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xinxin Gan
- Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wenliang Gong
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhenjie Wu
- Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Bing Liu
- Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Yi Bao
- Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Jie Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China.,Department of Urology, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Linhui Wang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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24
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Smith RL, Goddard A, Boddapati A, Brooks S, Schoeman JP, Lack J, Leisewitz A, Ackerman H. Experimental Babesia rossi infection induces hemolytic, metabolic, and viral response pathways in the canine host. BMC Genomics 2021; 22:619. [PMID: 34399690 PMCID: PMC8369750 DOI: 10.1186/s12864-021-07889-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/13/2021] [Indexed: 12/02/2022] Open
Abstract
Background Babesia rossi is a leading cause of morbidity and mortality among the canine population of sub-Saharan Africa, but pathogenesis remains poorly understood. Previous studies of B. rossi infection were derived from clinical cases, in which neither the onset of infection nor the infectious inoculum was known. Here, we performed controlled B. rossi inoculations in canines and evaluated disease progression through clinical tests and whole blood transcriptomic profiling. Results Two subjects were administered a low inoculum (104 parasites) while three received a high (108 parasites). Subjects were monitored for 8 consecutive days; anti-parasite treatment with diminazene aceturate was administered on day 4. Blood was drawn prior to inoculation as well as every experimental day for assessment of clinical parameters and transcriptomic profiles. The model recapitulated natural disease manifestations including anemia, acidosis, inflammation and behavioral changes. Rate of disease onset and clinical severity were proportional to the inoculum. To analyze the temporal dynamics of the transcriptomic host response, we sequenced mRNA extracted from whole blood drawn on days 0, 1, 3, 4, 6, and 8. Differential gene expression, hierarchical clustering, and pathway enrichment analyses identified genes and pathways involved in response to hemolysis, metabolic changes, and several arms of the immune response including innate immunity, adaptive immunity, and response to viral infection. Conclusions This work comprehensively characterizes the clinical and transcriptomic progression of B. rossi infection in canines, thus establishing a large mammalian model of severe hemoprotozoal disease to facilitate the study of host-parasite biology and in which to test novel anti-disease therapeutics. The knowledge gained from the study of B. rossi in canines will not only improve our understanding of this emerging infectious disease threat in domestic dogs, but also provide insight into the pathobiology of human diseases caused by Babesia and Plasmodium species. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07889-4.
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Affiliation(s)
- Rachel L Smith
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, MD, 20852, USA
| | - Amelia Goddard
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria, 0110, South Africa
| | - Arun Boddapati
- NIAID Collaborative Bioinformatics Resource (NCBR), National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20894, USA.,Advanced Biomedical Computational Science (ABCS), Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA
| | - Steven Brooks
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, MD, 20852, USA
| | - Johan P Schoeman
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria, 0110, South Africa
| | - Justin Lack
- NIAID Collaborative Bioinformatics Resource (NCBR), National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20894, USA.,Advanced Biomedical Computational Science (ABCS), Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA
| | - Andrew Leisewitz
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, Pretoria, 0110, South Africa.
| | - Hans Ackerman
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Rockville, MD, 20852, USA.
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25
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Kostallari E, Valainathan S, Biquard L, Shah VH, Rautou PE. Role of extracellular vesicles in liver diseases and their therapeutic potential. Adv Drug Deliv Rev 2021; 175:113816. [PMID: 34087329 PMCID: PMC10798367 DOI: 10.1016/j.addr.2021.05.026] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/29/2021] [Indexed: 02/07/2023]
Abstract
More than eight hundred million people worldwide have chronic liver disease, with two million deaths per year. Recurring liver injury results in fibrogenesis, progressing towards cirrhosis, for which there doesn't exists any cure except liver transplantation. Better understanding of the mechanisms leading to cirrhosis and its complications is needed to develop effective therapies. Extracellular vesicles (EVs) are released by cells and are important for cell-to-cell communication. EVs have been reported to be involved in homeostasis maintenance, as well as in liver diseases. In this review, we present current knowledge on the role of EVs in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, primary liver cancers, acute liver injury and liver regeneration. Moreover, therapeutic strategies involving EVs as targets or as tools to treat liver diseases are summarized.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Shantha Valainathan
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France
| | - Louise Biquard
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Pierre-Emmanuel Rautou
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
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26
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The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy. Cancer Lett 2021; 510:67-78. [PMID: 33895262 DOI: 10.1016/j.canlet.2021.04.011] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 03/31/2021] [Accepted: 04/15/2021] [Indexed: 12/20/2022]
Abstract
Immune checkpoint blockade has shown unprecedented and durable clinical response in a wide range of cancers. T cell immunoglobulin and mucin domain 3 (TIM3) is an inhibitory checkpoint protein that is highly expressed in tumor-infiltrating lymphocytes. In various cancers, the interaction of TIM3 and Galectin 9 (Gal9) suppresses anti-tumor immunity mediated by innate as well as adaptive immune cells. Thus, the blockade of the TIM3/Gal9 interaction is a promising therapeutic approach for cancer therapy. In addition, co-blockade of the TIM3/Gal9 pathway along with the PD-1/PD-L1 pathway increases the therapeutic efficacy by overcoming non-redundant immune resistance induced by each checkpoint. Here, we summarize the physiological roles of the TIM3/Gal9 pathway in adaptive and innate immune systems. We highlight the recent clinical and preclinical studies showing the involvement of the TIM3/Gal9 pathway in various solid and blood cancers. In addition, we discuss the potential of using TIM3 and Gal9 as prognostic and predictive biomarkers in different cancers. An in-depth mechanistic understanding of the blockade of the TIM3/Gal9 signaling pathway in cancer could help in identifying patients who respond to this therapy as well as designing combination therapies.
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27
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Patel H, Ashton NJ, Dobson RJB, Andersson LM, Yilmaz A, Blennow K, Gisslen M, Zetterberg H. Proteomic blood profiling in mild, severe and critical COVID-19 patients. Sci Rep 2021; 11:6357. [PMID: 33737684 PMCID: PMC7973581 DOI: 10.1038/s41598-021-85877-0] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 03/08/2021] [Indexed: 01/08/2023] Open
Abstract
The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.
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Affiliation(s)
- Hamel Patel
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
- NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK.
| | - Nicholas J Ashton
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
- Department of Psychiatry and Neurochemistry, Wallenberg Centre for Molecular and Translational Medicine, Institute of Neuroscience and Physiology, the SAHLGRENSKA Academy at the University of Gothenburg, Sahlgrenska University Hospital, MedTech West, Röda stråket 10B, 413 45, Göteborg, Sweden
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK
| | - Richard J B Dobson
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, SE5 8AF, UK
- UK Dementia Research Institute at UCL, London, UK
- Health Data Research UK London, University College London, 222 Euston Road, London, UK
- Institute of Health Informatics, University College London, 222 Euston Road, London, UK
- The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, 222 Euston Road, London, UK
| | - Lars-Magnus Andersson
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Aylin Yilmaz
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Magnus Gisslen
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
- UK Dementia Research Institute at UCL, London, UK
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28
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Iwasaki-Hozumi H, Chagan-Yasutan H, Ashino Y, Hattori T. Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases. Biomolecules 2021; 11:biom11030430. [PMID: 33804076 PMCID: PMC7998537 DOI: 10.3390/biom11030430] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Galectin-9 (Gal-9) is a β-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.
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Affiliation(s)
- Hiroko Iwasaki-Hozumi
- Department of Health Science and Social Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (H.C.-Y.)
| | - Haorile Chagan-Yasutan
- Department of Health Science and Social Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (H.C.-Y.)
- Mongolian Psychosomatic Medicine Department, International Mongolian Medicine Hospital of Inner Mongolia, Hohhot 010065, China
| | - Yugo Ashino
- Department of Respiratory Medicine, Sendai City Hospital, Sendai 982-8502, Japan;
| | - Toshio Hattori
- Department of Health Science and Social Welfare, Kibi International University, Takahashi 716-8508, Japan; (H.I.-H.); (H.C.-Y.)
- Correspondence: ; Tel.: +81-866-22-9454
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Sagaya Jansi R, Khusro A, Agastian P, Alfarhan A, Al-Dhabi NA, Arasu MV, Rajagopal R, Barcelo D, Al-Tamimi A. Emerging paradigms of viral diseases and paramount role of natural resources as antiviral agents. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 759:143539. [PMID: 33234268 PMCID: PMC7833357 DOI: 10.1016/j.scitotenv.2020.143539] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/14/2020] [Accepted: 10/17/2020] [Indexed: 05/04/2023]
Abstract
In the current scenario, the increasing prevalence of diverse microbial infections as well as emergence and re-emergence of viral epidemics with high morbidity and mortality rates are major public health threat. Despite the persistent production of antiviral drugs and vaccines in the global market, viruses still remain as one of the leading causes of deadly human diseases. Effective control of viral diseases, particularly Zika virus disease, Nipah virus disease, Severe acute respiratory syndrome, Coronavirus disease, Herpes simplex virus infection, Acquired immunodeficiency syndrome, and Ebola virus disease remain promising goal amidst the mutating viral strains. Current trends in the development of antiviral drugs focus solely on testing novel drugs or repurposing drugs against potential targets of the viruses. Compared to synthetic drugs, medicines from natural resources offer less side-effect to humans and are often cost-effective in the productivity approaches. This review intends not only to emphasize on the major viral disease outbreaks in the past few decades and but also explores the potentialities of natural substances as antiviral traits to combat viral pathogens. Here, we spotlighted a comprehensive overview of antiviral components present in varied natural sources, including plants, fungi, and microorganisms in order to identify potent antiviral agents for developing alternative therapy in future.
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Affiliation(s)
- R Sagaya Jansi
- Department of Bioinformatics, Stella Maris College, Chennai, India
| | - Ameer Khusro
- Department of Plant Biology and Biotechnology, Loyola College, Chennai, India
| | - Paul Agastian
- Department of Plant Biology and Biotechnology, Loyola College, Chennai, India.
| | - Ahmed Alfarhan
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia.
| | - Naif Abdullah Al-Dhabi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mariadhas Valan Arasu
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Rajakrishnan Rajagopal
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Damia Barcelo
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia; Water and Soil Research Group, Department of Environmental Chemistry, IDAEA-CSIC, JORDI GIRONA 18-26, 08034 Barcelona, Spain
| | - Amal Al-Tamimi
- Ecology Department, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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Moar P, Tandon R. Galectin-9 as a biomarker of disease severity. Cell Immunol 2021; 361:104287. [PMID: 33494007 DOI: 10.1016/j.cellimm.2021.104287] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/26/2020] [Accepted: 01/09/2021] [Indexed: 12/16/2022]
Abstract
Galectin-9 (Gal-9) is a β-galactoside binding lectin known for its immunomodulatory role in various microbial infections. Gal-9 is expressed in all organ systems and localized in the nucleus, cell surface, cytoplasm and the extracellular matrix. It mediates host-pathogen interactions and regulates cell signalling via binding to its receptors. Gal-9 is involved in many physiological functions such as cell growth, differentiation, adhesion, communication and death. However, recent studies have emphasized on the elevated levels of Gal-9 in autoimmune disorders, viral infections, parasitic invasion, cancer, acute liver failure, atopic dermatitis, chronic kidney disease, type-2 diabetes, coronary artery disease, atherosclerosis and benign infertility-related gynecological disorders. In this paper we have reviewed the potential of Gal-9 as a reliable, sensitive and non-invasive biomarker of disease severity. Tracking changes in Gal-9 levels and its implementation as a biomarker in clinical practice will be an important tool to monitor disease activity and facilitate personalized treatment decisions.
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Affiliation(s)
- Preeti Moar
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
| | - Ravi Tandon
- Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
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31
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Lim HK, Jeffrey GP, Ramm GA, Soekmadji C. Pathogenesis of Viral Hepatitis-Induced Chronic Liver Disease: Role of Extracellular Vesicles. Front Cell Infect Microbiol 2020; 10:587628. [PMID: 33240824 PMCID: PMC7683521 DOI: 10.3389/fcimb.2020.587628] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles are encapsulated lipid nanoparticles secreted by a variety of cell types in living organisms. They are known to carry proteins, metabolites, nucleic acids, and lipids as their cargoes and are important mediators of intercellular communication. The role of extracellular vesicles in chronic liver disease has been reported. Chronic liver disease such as viral hepatitis accounts for a significant mortality and morbidity burden worldwide. Hepatic fibrosis has been commonly associated with the chronic form of viral hepatitis, which results in end-stage liver disease, including cirrhosis, liver failure, and carcinoma in some patients. In this review, we discuss the potential role of extracellular vesicles in mediating communication between infectious agents (hepatitis B and C viruses) and host cells, and how these complex cell-cell interactions may facilitate the development of chronic liver disease. We will further discuss how understanding their biological mechanism of action might be beneficial for developing therapeutic strategies to treat chronic liver disease.
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Affiliation(s)
- Hong Kiat Lim
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Gary P Jeffrey
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.,Sir Charles Gairdner Hospital, Nedlands, Hepatology Department and Liver Transplant Service, Perth, WA, Australia
| | - Grant A Ramm
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Carolina Soekmadji
- Hepatic Fibrosis Group, Department of Cellular and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal. Int J Mol Sci 2020; 21:ijms21207473. [PMID: 33050486 PMCID: PMC7589490 DOI: 10.3390/ijms21207473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.
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Okwor CIA, Oh JS, Crawley AM, Cooper CL, Lee SH. Expression of Inhibitory Receptors on T and NK Cells Defines Immunological Phenotypes of HCV Patients with Advanced Liver Fibrosis. iScience 2020; 23:101513. [PMID: 32920488 PMCID: PMC7492990 DOI: 10.1016/j.isci.2020.101513] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 07/23/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic HCV can result in advanced liver disease, including cirrhosis. Patients with advanced fibrosis experience poor clinical outcomes and increased risk for hepatocellular carcinoma (HCC). These outcomes are, in part, a consequence of immune dysfunction. Increased inhibitory receptor and Galectin-9 (GAL-9) expression is a possible mechanism promoting lymphocyte dysfunction. In this study, we measured the expression of inhibitory receptors and GAL-9 on T/NK cells of patients with chronic HCV with no to moderate fibrosis (F0-F2) and advanced fibrosis (F3-F4). To analyze their co-expression, we employed t-SNE analysis. Notably, we found that F3-F4 patients had higher frequencies of >3 inhibitory receptor co-expression on NK cells. Moreover, F3-F4 patients manifest a higher frequency of NK cells co-expressing TIGIT and TIM-3, and CD4/NK cells co-expressing LAG-3 and GAL-9. In conclusion, we identified phenotypes of immune dysregulation that could explain the increased susceptibility to infection and HCC in patients with chronic HCV with advanced fibrosis.
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Affiliation(s)
| | - Jun Seok Oh
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
| | - Angela Marie Crawley
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Department of Biology, Carleton University, Ottawa K1S 5B6, Canada
| | - Curtis Lindsey Cooper
- Division of Infectious Diseases, Ottawa Hospital-General Campus, Ottawa K1H 8L6, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa K1Y 4E9, Canada
- Department of Medicine, University of Ottawa, Ottawa K1H 8M5, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa K1G 5Z3, Canada
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada
- The University of Ottawa Centre for Infection, Immunity, and Inflammation, Ottawa K1H 8M5, Canada
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Rosen HR, Golden-Mason L. Control of HCV Infection by Natural Killer Cells and Macrophages. Cold Spring Harb Perspect Med 2020; 10:a037101. [PMID: 31871225 PMCID: PMC7447067 DOI: 10.1101/cshperspect.a037101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Host defense against invading pathogens within the liver is dominated by innate immunity. Natural killer (NK) cells have been implicated at all stages of hepatitis C virus (HCV) infection, from providing innate protection to contributing to treatment-induced clearance. Decreased NK cell levels, altered NK cell subset distribution, activation marker expression, and functional polarization toward a cytolytic phenotype are hallmarks of chronic HCV infection. Interferon α (IFN-α) is a potent activator of NK cells; therefore, it is not surprising that NK cell activation has been identified as a key factor associated with sustained virological response (SVR) to IFN-α-based therapies. Understanding the role of NK cells, macrophages, and other innate immune cells post-SVR remains paramount for prevention of disease pathogenesis and progression. Novel strategies to treat liver disease may be aimed at targeting these cells.
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Affiliation(s)
- Hugo R Rosen
- Department of Medicine, University of Southern California (USC), Los Angeles, California 90033, USA
- USC Research Center for Liver Diseases, Los Angeles, California 90033, USA
| | - Lucy Golden-Mason
- Department of Medicine, University of Southern California (USC), Los Angeles, California 90033, USA
- USC Research Center for Liver Diseases, Los Angeles, California 90033, USA
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36
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Sun MJ, Cao ZQ, Leng P. The roles of galectins in hepatic diseases. J Mol Histol 2020; 51:473-484. [PMID: 32734557 DOI: 10.1007/s10735-020-09898-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 07/14/2020] [Indexed: 12/24/2022]
Abstract
Hepatic diseases include all diseases that occur in the liver, including hepatitis, cirrhosis, hepatocellular carcinoma, etc. Hepatic diseases worldwide are characterized by high incidences of digestive system diseases, which present with subtle symptoms, are difficult to treat and have high mortality. Galectins are β-galactoside-binding proteins that have been found to be aberrantly expressed during hepatic disease progression. An increasing number of studies have shown that abnormal expression of galectins is extensively involved in hepatic diseases, such as hepatocellular carcinoma (HCC), liver cirrhosis, hepatitis and liver fibrosis. Galectins function as intracellular and extracellular hepatic disease regulators mainly through the binding of their carbohydrate recognition domain to glycoconjugates expressed in hepatocytes. In this review, we summarize current research on the various roles of galectins in cirrhosis, hepatitis, liver fibrosis and HCC, which may provide a preliminary theoretical basis for the exploration of new targets for the treatment of hepatic diseases.
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Affiliation(s)
- Mei-Juan Sun
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China
| | - Zhan-Qi Cao
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China
| | - Ping Leng
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiang Su Road, Qingdao, 266003, People's Republic of China.
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Shete A, Dhayarkar S, Dhamanage A, Kulkarni S, Ghate M, Sangle S, Medhe U, Verma V, Rajan S, Hattori T, Gangakhedkar R. Possible role of plasma Galectin-9 levels as a surrogate marker of viremia in HIV infected patients on antiretroviral therapy in resource-limited settings. AIDS Res Ther 2020; 17:43. [PMID: 32678033 PMCID: PMC7364535 DOI: 10.1186/s12981-020-00298-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 07/07/2020] [Indexed: 01/09/2023] Open
Abstract
Background Early detection of viremia in HIV infected patients on anti-retroviral therapy (ART) is important to prevent disease progression as well as accumulation of drug resistance mutations. This makes HIV viral load (VL) monitoring indispensable in HIV infected patients on ART. However VL, being an expensive test, results in heavy financial burden on health services. Hence, cheaper surrogate markers of viremia are desired to reduce overall cost of management of HIV infected patients. Methods We enrolled aviremic (n = 63, M:F = 31:32) and viremic (n = 43, M:F = 21:22) HIV infected patients at 1 year after ART initiation. Viremic individuals were identified as those having a plasma VL of more than 1000 copies/µl and aviremic individuals as less than 40 copies/µl. The study participants also included immuno-virologically discordant patients as they demonstrate differential degrees of immune-reconstitution and are likely to harbour concomitant infections influencing levels of immune-activation markers screened as the surrogate markers. Immune activation markers viz. plasma hs-CRP, soluble-CD14 and Galectin-9 levels were estimated by ELISA, IL-6 by luminex assay and percentages of CD38+ CD8+ cells were determined by flow cytometry. The levels were compared between viremic and aviremic patients and correlated with plasma viral load. Receiver operated curve (ROC) analysis was done for plasma Galectin-9 levels. Results Viremic patients had significantly higher levels of Galectin-9 and %CD38+ CD8+ cells (p values < 0.0001) than aviremic patients. Levels of the other activation markers did not differ between viremic and aviremic individuals. Galectin-9 levels (r = 0.76) and %CD38+ CD8+ cells (r = 0.39) correlated positively with VL. Area under curve for Galectin-9 levels for distinguishing between viremic and aviremic individuals was 0.98. Youden index, sensitivity, specificity, positive predictive value and negative predictive value for Galectin-9 levels were 0.87, 0.97, 0.90, 0.87 and 0.98, respectively, at the cut-off value of 5.79 ng/ml. Conclusions Plasma Galectin-9 levels could identify viremic individuals with sensitivity and specificity of more than 90%. Thus, they showed a potential to serve as a surrogate marker of viremia in HIV infected patients on ART and would have cost implications on HIV management especially in resource-limited settings. However, the findings need to be confirmed in the patients on ART for different durations of time.
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Sepulveda-Crespo D, Resino S, Martinez I. Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants. Vaccines (Basel) 2020; 8:vaccines8020313. [PMID: 32560440 PMCID: PMC7350220 DOI: 10.3390/vaccines8020313] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/12/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023] Open
Abstract
Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.
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Affiliation(s)
| | - Salvador Resino
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
| | - Isidoro Martinez
- Correspondence: (S.R.); (I.M.); Tel.: +34-91-8223266 (S.R.); +34-91-8223272 (I.M.); Fax: +34-91-5097919 (S.R. & I.M.)
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Hakim MS, Jariah ROA, Spaan M, Boonstra A. Interleukin 15 upregulates the expression of PD-1 and TIM-3 on CD4 + and CD8 + T cells. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2020; 9:10-21. [PMID: 32704430 PMCID: PMC7364376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/28/2020] [Indexed: 06/11/2023]
Abstract
Virus-specific T cell-mediated immunity is severely impaired in chronic hepatitis B virus (HBV) patients. HBV-specific T cells in chronic HBV patients show a low ability to produce cytokines and to exert their cytotoxic activity. A prominent characteristic of these exhausted T cells is overexpression of inhibitory receptor molecules which negatively regulate T cell function. In this study, we examined in vitro regulation of two inhibitory receptor expressions, programmed death 1 (PD-1) and T cell immunoglobulin mucin domain-containing molecule 3 (TIM-3). Peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals were in vitro stimulated with a panel of cytokines. PD-1 and TIM-3 expression levels on CD4+ and CD8+ T cells were examined at days 2 and 7 post stimulation. We demonstrated that PD-1 and TIM-3 were induced via polyclonal (anti-CD3) and cytokine (interleukin 15 [IL-15]) stimulations. Noteworthy, there was a significantly increased induction of TIM-3 on CD8+ T cells as compared to CD4+ T cells. Our study thus contributes to further understanding the regulation of T cell exhaustion markers PD-1 and TIM-3.
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Affiliation(s)
- Mohamad S Hakim
- Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah MadaYogyakarta, Indonesia
- Postgraduate School of Molecular Medicine, Erasmus MC-University Medical Center RotterdamThe Netherlands
| | - Rizka O A Jariah
- Department of Health Science, Faculty of Vocational Studies, Universitas AirlanggaSurabaya, Indonesia
| | - Michelle Spaan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center RotterdamThe Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center RotterdamThe Netherlands
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40
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Tim-3: A co-receptor with diverse roles in T cell exhaustion and tolerance. Semin Immunol 2020; 42:101302. [PMID: 31604535 DOI: 10.1016/j.smim.2019.101302] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 08/30/2019] [Indexed: 12/13/2022]
Abstract
T cell inhibitory co-receptors play a crucial role in maintaining the balance between physiologic immune responses and maladaptive ones. T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is a unique inhibitory co-receptor in that its expression is chiefly restricted to interferon (IFN)γ-producing CD4+ and CD8+ T cells. Early reports firmly established its importance in maintaining peripheral tolerance in transplantation and autoimmunity. However, it has become increasingly clear that Tim-3 expression on T cells, together with other check-point molecules, in chronic infections and cancers can hinder productive immune responses. In this review, we outline what is currently known about the regulation of Tim-3 expression, its ligands and signaling. We discuss both its salutary and deleterious function in immune disorders, as well as the T cell-extrinsic and -intrinsic factors that regulate its function.
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41
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Szereday L, Meggyes M, Berki T, Miseta A, Farkas N, Gervain J, Par A, Par G. Direct-acting antiviral treatment downregulates immune checkpoint inhibitor expression in patients with chronic hepatitis C. Clin Exp Med 2020; 20:219-230. [PMID: 32108916 PMCID: PMC7181552 DOI: 10.1007/s10238-020-00618-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis C (CHC) infection is associated with increased TIM-3, PD-1 immune checkpoint receptors expression that inhibits adaptive T cells and increases NK cell cytotoxicity against T helper cells, both resulting T cell exhaustion. Elimination of the virus with direct-acting antivirals (DAAs) may modify host immune response via altering these immune checkpoint receptors’ expression. We conducted a prospective study to analyze changes in TIM-3, PD-1 and their ligands galectin-9, PD-L1 expression by peripheral blood T cell subpopulations, NK cell subpopulations, and monocytes by multicolor flow cytometry in 14 CHC patients successfully treated with 12 weeks of dasabuvir, ombitasvir, and paritaprevir/ritonavir plus ribavirin. Blood samples were collected before, at the end of treatment, and 12 and 24 weeks later. Sustained virological response (SVR) was associated with increased percentage of peripheral blood CD3+ T and CD8+ cytotoxic T lymphocytes and decreased percentage of NKbright cells. After DAA treatment, decreased TIM-3 expression by CD4+ T cells, by NKbright, and by NKT cells was found. Expression of immune checkpoint molecules’ ligand PD-L1 by NK cells and by regulatory T cells and galectin-9 by NK cells and monocytes also decreased significantly at SVR. Our data suggest that DAA treatment not only inhibits viral replication but may alter host adaptive and innate immune responses. A decrease in immune checkpoint molecules and their ligands expression both on adaptive and on innate immune cells may contribute to the recovery of exhausted adaptive immune responses and to sustained virological response.
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Affiliation(s)
- Laszlo Szereday
- Department of Medical Microbiology and Immunology, University of Pecs, Medical School, 12 Szigeti Street, Pecs, 7624, Hungary. .,Janos Szentagothai Research Centre, Pecs, Hungary.
| | - Matyas Meggyes
- Department of Medical Microbiology and Immunology, University of Pecs, Medical School, 12 Szigeti Street, Pecs, 7624, Hungary.,Janos Szentagothai Research Centre, Pecs, Hungary
| | - Timea Berki
- Department of Biotechnology and Immunology, University of Pecs, Medical School, Pecs, Hungary
| | - Attila Miseta
- Department of Laboratory Medicine, University of Pecs, Medical School, Pecs, Hungary
| | - Nelli Farkas
- Institute for Translational Medicine, University of Pecs, Medical School, Pecs, Hungary
| | - Judit Gervain
- County Hospital Fejér, Szent György Hospital, Szekesfehervar, Hungary
| | - Alajos Par
- Division of Gastroenterology, First Department of Medicine, University of Pecs, Medical School, Pecs, Hungary
| | - Gabriella Par
- Institute for Translational Medicine, University of Pecs, Medical School, Pecs, Hungary.,Division of Gastroenterology, First Department of Medicine, University of Pecs, Medical School, Pecs, Hungary
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Zhao L, Yu G, Han Q, Cui C, Zhang B. TIM-3: An emerging target in the liver diseases. Scand J Immunol 2020; 91:e12825. [PMID: 31486085 DOI: 10.1111/sji.12825] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/27/2019] [Accepted: 08/31/2019] [Indexed: 12/17/2022]
Abstract
T cell immunoglobulin domain and mucin domain-containing molecule 3 (TIM-3) is found expression in the surface of terminally differentiated T cells and belongs to the TIM family of type Ⅰ transmembrane proteins. It binds to the ligand Galectin-9 and mediates T cell apoptosis. As the research progresses, TIM-3 is also expressed in Th17, NK, monocyte, which binds to ligand and induce immune peripheral tolerance in both mice and man. Numerous researches have demonstrated that TIM-3 influences liver diseases, including liver-associated chronic viral infection, liver fibrosis, liver cancer et al and suggest new approaches to intervention. Currently, targeted therapy of TIM-3 is a new treatment in the field of immunization. Although many studies have proven that TIM-3 has an inhibitory effect in vivo, the specific mechanism is not clear. Herein, we summarize the important role of TIM-3 in the regulation of liver disease and prospects for future clinical research. TIM-3 will provide new targets for improving clinical liver disease.
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Affiliation(s)
- Lizhen Zhao
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
| | - Guoyi Yu
- Editorial Office of Journal of Qingdao University (Medical Science), Qingdao, China
| | - Qi Han
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
| | - Congxian Cui
- Affiliated Hospital of Qingdao University Medical College, Qingdao, China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
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43
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Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 2019; 38:396. [PMID: 31500650 PMCID: PMC6734524 DOI: 10.1186/s13046-019-1396-4] [Citation(s) in RCA: 298] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.
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MESH Headings
- Adaptive Immunity
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Antineoplastic Agents, Immunological/therapeutic use
- Biomarkers, Tumor
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Clinical Trials as Topic
- Combined Modality Therapy/methods
- Humans
- Immunity, Innate
- Immunotherapy/adverse effects
- Immunotherapy/methods
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Translational Research, Biomedical
- Treatment Outcome
- Tumor Microenvironment/immunology
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Affiliation(s)
- Yaojie Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shanshan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008 Hunan China
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44
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Circulating levels of PD-L1 and Galectin-9 are associated with patient survival in surgically treated Hepatocellular Carcinoma independent of their intra-tumoral expression levels. Sci Rep 2019; 9:10677. [PMID: 31337865 PMCID: PMC6650499 DOI: 10.1038/s41598-019-47235-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 07/15/2019] [Indexed: 02/07/2023] Open
Abstract
Tumor expression of immune co-inhibitory ligands, such as PD-L1 and Galectin-9, have potential prognostic value in Hepatocellular Carcinoma (HCC). Circulating levels of these molecules, however, have hardly been studied. This study aims to assess the prognostic significance of circulating PD-L1 and circulating Galectin-9 in patients with resected HCC, and to compare their prognostic significance to the intra-tumoral expression of these same molecules. Archived tissues and stored peripheral blood samples from 81 patients who underwent HCC resection or liver transplantation, with curative intent, were used. Immunohistochemistry was performed to determine intra-tumoral expression of PD-L1 and Galectin-9, while ELISA was used to quantify their respective circulating levels. High circulating PD-L1 (HR 0.12, 95%CI 0.16-0.86, p = 0.011) and high circulating Galectin-9 (HR 0.11, 95%CI 0.15-0.85, p = 0.010) levels were both associated with improved HCC-specific survival. Surprisingly, there was no correlation between circulating levels of PD-L1 and Galectin-9 and their intra-tumoral expression levels. In fact, circulating levels of PD-L1 and Galectin-9 were predictive of HCC-specific survival independently of intra-tumoral levels and baseline clinicopathologic characteristics. Combined analysis of circulating levels and intra-tumoral expression of PD-L1 (HR 0.33, 95%CI 0.16-0.68, p = 0.002) and Galectin-9 (HR 0.27, 95%CI 0.13-0.57, p = 0.001) resulted in more confident prediction of survival. In conclusion, circulating PD-L1 and Galectin-9 levels prognostically differentiate resected HCC patients, independently of their intra-tumoral expression. Combining circulating and intra-tumoral expression levels of PD-L1 or Galectin-9 further improves the prognostic values of these immune biomarkers.
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45
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Chen X, Wang L, Deng Y, Li X, Li G, Zhou J, Cheng D, Yang Y, Yang Q, Chen G, Wang G. Inhibition of Autophagy Prolongs Recipient Survival Through Promoting CD8 + T Cell Apoptosis in a Rat Liver Transplantation Model. Front Immunol 2019; 10:1356. [PMID: 31258533 PMCID: PMC6587890 DOI: 10.3389/fimmu.2019.01356] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/29/2019] [Indexed: 12/13/2022] Open
Abstract
In liver transplantation (LT), although various immunosuppressants have been used in clinical practice, acute rejection remains a common complication that significantly shortens recipient survival. In recent years, manipulating immune tolerance has been regarded as one of the promising solutions to rejection. Autophagy, an evolutionarily conserved protein degradation system, has been reported to be involved in immune rejection and may be a target to establish immune tolerance. However, the role of autophagy in acute rejection reaction after LT has not been elucidated. Here, we showed that the autophagy of CD8+ T cells was strongly enhanced in patients with graft rejection and that the autophagy level was positively correlated with the severity of rejection. Similar findings were observed in a rat acute hepatic rejection model. Furthermore, administration of the autophagy inhibitor 3-methyladenine (3-MA) largely decreased the viability and function of CD8+ T cells through inhibiting autophagy, which significantly prolonged graft survival in rats. In addition, inhibiting the autophagy of activated CD8+ T cells in vitro considerably suppressed mitochondria mediated survival and downregulated T cell function. Conclusions: We first showed that the inhibition of autophagy significantly prolongs liver allograft survival by promoting the apoptosis of CD8+ T cells, which may provide a novel strategy for immune tolerance induction.
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Affiliation(s)
- Xiaolong Chen
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Wang
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yinan Deng
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xuejiao Li
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guolin Li
- Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jing Zhou
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Daorou Cheng
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Yang
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qing Yang
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guihua Chen
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Genshu Wang
- Department of Hepatic Surgery, Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Chiyo T, Fujita K, Iwama H, Fujihara S, Tadokoro T, Ohura K, Matsui T, Goda Y, Kobayashi N, Nishiyama N, Yachida T, Morishita A, Kobara H, Mori H, Niki T, Hirashima M, Himoto T, Masaki T. Galectin-9 Induces Mitochondria-Mediated Apoptosis of Esophageal Cancer In Vitro and In Vivo in a Xenograft Mouse Model. Int J Mol Sci 2019; 20:ijms20112634. [PMID: 31146370 PMCID: PMC6600680 DOI: 10.3390/ijms20112634] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/20/2019] [Accepted: 05/24/2019] [Indexed: 12/30/2022] Open
Abstract
Galectin-9 (Gal-9) enhances tumor immunity mediated by T cells, macrophages, and dendritic cells. Its expression level in various cancers correlates with prognosis. Furthermore, Gal-9 directly induces apoptosis in various cancers; however, its mechanism of action and bioactivity has not been clarified. We evaluated Gal-9 antitumor effect against esophageal squamous cell carcinoma (ESCC) to analyze the dynamics of apoptosis-related molecules, elucidate its mechanism of action, and identify relevant changes in miRNA expressions. KYSE-150 and KYSE-180 cells were treated with Gal-9 and their proliferation was evaluated. Gal-9 inhibited cell proliferation in a concentration-dependent manner. The xenograft mouse model established with KYSE-150 cells was administered with Gal-9 and significant suppression in the tumor growth observed. Gal-9 treatment of KYSE-150 cells increased the number of Annexin V-positive cells, activation of caspase-3, and collapse of mitochondrial potential, indicating apoptosis induction. c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) phosphorylation were activated and could be involved in apoptosis. Therefore, Gal-9 induces mitochondria-mediated apoptosis of ESCC and inhibits cell proliferation in vitro and in vivo with JNK and p38 activation.
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Affiliation(s)
- Taiga Chiyo
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Kyoko Ohura
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Takanori Matsui
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Yasuhiro Goda
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Nobuya Kobayashi
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Noriko Nishiyama
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Tatsuo Yachida
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Hirohito Mori
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Toshiro Niki
- Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Mitsuomi Hirashima
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan.
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
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Valdivieso A, Ribas L, Piferrer F. Ovarian transcriptomic signatures of zebrafish females resistant to different environmental perturbations. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2019; 332:55-68. [DOI: 10.1002/jez.b.22848] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/06/2019] [Indexed: 11/10/2022]
Affiliation(s)
- Alejandro Valdivieso
- Institut de Ciències del Mar (ICM)Consejo Superior de Investigaciones Científicas (CSIC)Barcelona Spain
| | - Laia Ribas
- Institut de Ciències del Mar (ICM)Consejo Superior de Investigaciones Científicas (CSIC)Barcelona Spain
| | - Francesc Piferrer
- Institut de Ciències del Mar (ICM)Consejo Superior de Investigaciones Científicas (CSIC)Barcelona Spain
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48
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Wang J, Li C, Fu J, Wang X, Feng X, Pan X. Tim-3 regulates inflammatory cytokine expression and Th17 cell response induced by monocytes from patients with chronic hepatitis B. Scand J Immunol 2019; 89:e12755. [PMID: 30729555 DOI: 10.1111/sji.12755] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 02/02/2019] [Accepted: 02/03/2019] [Indexed: 02/06/2023]
Abstract
Tim-3 is expressed on monocytes/macrophages and is involved in the regulation of inflammatory responses. The aim of this study was to determine the effect of Tim-3 on inflammatory response triggered by peripheral monocytes from patients with chronic hepatitis B (CHB). Tim-3 expression on peripheral monocytes and frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) derived from CHB patients were detected. Followed by lipopolysaccharides (LPS) activation of circulating monocytes from CHB patients, expression of inflammatory cytokines including TNF-α,IL-1β and IL-6 were examined in the presence and absence of Galectin-9 which is the ligand for Tim-3. Subsequently, after purified CD4+T cells were cocultured with LPS-activated monocytes from CHB patients in the presence of anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 were measured. Tim-3 expression was significantly upregulated and closely correlated to the frequency of Th17 cells in patients with CHB. Expression of TNF-α,IL-1β and IL-6 increased significantly in monocytes stimulated with LPS and Galectin-9, compared to LPS stimulation alone. LPS-activated monocytes from CHB patients could drive differentiation of memory CD4+T cells to Th17 cells. However, under the blockade of Tim-3 signalling by anti-Tim-3 antibody, percentage of Th17 cells and production of IL-17 decreased significantly. Our results demonstrate that upregulated expression of Tim-3 on circulating monocytes accelerates inflammatory response by promoting production of inflammatory cytokines and Th17 responses in CHB.
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Affiliation(s)
- Junyan Wang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chan Li
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Juanjuan Fu
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xia Wang
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xia Feng
- Central Laboratory of the Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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49
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Restriction of Human Cytomegalovirus Infection by Galectin-9. J Virol 2019; 93:JVI.01746-18. [PMID: 30487283 DOI: 10.1128/jvi.01746-18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 10/31/2018] [Indexed: 12/24/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus. While HCMV infection is generally asymptomatic in the immunocompetent, it can have devastating consequences in those with compromised or underdeveloped immune systems, including transplant recipients and neonates. Galectins are a widely expressed protein family that have been demonstrated to modulate both antiviral immunity and regulate direct host-virus interactions. The potential for galectins to directly modulate HCMV infection has not previously been studied, and our results reveal that galectin-9 (Gal-9) can potently inhibit HCMV infection. Gal-9-mediated inhibition of HCMV was dependent upon its carbohydrate recognition domains and thus dependent on glycan interactions. Temperature shift studies revealed that Gal-9 specific inhibition was mediated primarily at the level of virus-cell fusion and not binding. Additionally, we found that during reactivation of HCMV in hematopoietic stem cell transplant (HSCT) patients soluble Gal-9 is upregulated. This study provides the first evidence for Gal-9 functioning as a potent antiviral defense effector molecule against HCMV infection and identifies it as a potential clinical candidate to restrict HCMV infections.IMPORTANCE Human cytomegalovirus (HCMV) continues to cause serious and often life-threatening disease in those with impaired or underdeveloped immune systems. This virus is able to infect and replicate in a wide range of human cell types, which enables the virus to spread to other individuals in a number of settings. Current antiviral drugs are associated with a significant toxicity profile, and there is no vaccine; these factors highlight a need to identify additional targets for the development of anti-HCMV therapies. We demonstrate for the first time that secretion of a member of the galectin family of proteins, galectin-9 (Gal-9), is upregulated during natural HCMV-reactivated infection and that this soluble cellular protein possesses a potent capacity to block HCMV infection by inhibiting virus entry into the host cell. Our findings support the possibility of harnessing the antiviral properties of Gal-9 to prevent HCMV infection and disease.
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50
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Machala EA, McSharry BP, Rouse BT, Abendroth A, Slobedman B. Gal power: the diverse roles of galectins in regulating viral infections. J Gen Virol 2019; 100:333-349. [PMID: 30648945 DOI: 10.1099/jgv.0.001208] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Viruses, as a class of pathogenic microbe, remain a significant health burden globally. Viral infections result in significant morbidity and mortality annually and many remain in need of novel vaccine and anti-viral strategies. The development of effective novel anti-viral therapeutics, in particular, requires detailed understanding of the mechanism of viral infection, and the host response, including the innate and adaptive arms of the immune system. In recent years, the role of glycans and lectins in pathogen-host interactions has become an increasingly relevant issue. This review focuses on the interactions between a specific lectin family, galectins, and the broad range of viral infections in which they play a role. Discussed are the diverse activities that galectins play in interacting directly with virions or the cells they infect, to promote or inhibit viral infection. In addition we describe how galectin expression is regulated both transcriptionally and post-transcriptionally by viral infections. We also compare the contribution of known galectin-mediated immune modulation, across a range of innate and adaptive immune anti-viral responses, to the outcome of viral infections.
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Affiliation(s)
- Emily A Machala
- 1Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, New South Wales, Australia
| | - Brian P McSharry
- 1Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, New South Wales, Australia
| | - Barry T Rouse
- 2Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA
| | - Allison Abendroth
- 1Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, New South Wales, Australia
| | - Barry Slobedman
- 1Discipline of Infectious Diseases and Immunology, University of Sydney, Camperdown, New South Wales, Australia
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