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Zhu L, Liang Y, Yang L, Yang Q, Yin J, Wang T, Xu X, Zhang Q. Helicobacter mastomyrinus infection induces autoimmune hepatitis in mice. J Transl Autoimmun 2025; 10:100275. [PMID: 39981114 PMCID: PMC11840492 DOI: 10.1016/j.jtauto.2025.100275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/22/2025] [Indexed: 02/22/2025] Open
Abstract
Background Autoimmune hepatitis (AIH) is a chronic progressive liver disease caused by the immune system mistakenly attacking its own hepatocytes. The role of the gut microbiome in the pathogenesis and progression of AIH is of considerable significance. However, the dearth of suitable animal models has significantly constrained advancements in the pathogenesis and the development of therapeutic strategies for AIH. Helicobacter mastomyrinus (H. mastomyrinus, Hm) is a potentially zoonotic pathogenic microorganism capable of causing diseases of the enterohepatic system in rodent laboratory animals. Nevertheless, research on its role and mechanisms in causing liver disease is severely limited. Methods In this study, male BALB/c mice were infected with Hm isolate Hm-17, and were sacrificed at 4 w, 8 w, 14 w and 22 w after infection, respectively. The serum was collected for detecting a number of AIH indicators, including the aminotransferases level, IgG content and autoantibody level. Additionally, the liver tissue was examined for pathological analysis, fibrosis, bacterial content, and the distribution of immune cells. Results It was observed that the infection initially caused focal necrotizing hepatitis and subsequently progressed to interface hepatitis with lymphocyte/plasma cell infiltration, as well as hypergammaglobulinemia and autoantibody reactions, predominantly to Anti-nuclear and anti-smooth muscle antibodies. Furthermore, as the infection persisted, the mice exhibited a progressive increase in liver fibrosis and mild steatosis. Despite the maintenance of a low level of Hm colonization in the liver, there was a notable infiltrate of macrophages, T and B lymphocytes. In particular, the inflammatory foci in the Hm-infected liver were highly enriched for IL17+ cells. Conclusion The present study provides an animal model of immunological liver injury induced by Hm infection that exhibits main characteristics similar to those observed in AIH-1 patients. This model may serve as a novel animal model for the study of the pathogenesis and potential therapeutic strategies for human AIH.
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Affiliation(s)
- Liqi Zhu
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Yuanyuan Liang
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Linghan Yang
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Qihui Yang
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Jun Yin
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Tao Wang
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
| | - Xiangming Xu
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Taizhou University, Taizhou, China
| | - Quan Zhang
- College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China
- International Research Laboratory of Prevention and Control of Important Animal Infectious Diseases and Zoonotic Diseases of Jiangsu Higher Education Institutions, Yangzhou University, Yangzhou, China
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Wohlleber D, Knolle PA. Tissue Determinants of Antiviral Immunity in the Liver. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:65-72. [PMID: 39793603 PMCID: PMC11723797 DOI: 10.1055/a-2365-3900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 11/13/2024] [Indexed: 01/13/2025]
Abstract
The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.
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Affiliation(s)
- Dirk Wohlleber
- Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Percy A. Knolle
- Institute of Molecular Immunology, School of Life Science, Technical University of Munich, Munich, Germany
- German Center for Infection Research, Munich, Germany
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Han JW, Park SH. Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:257-272. [PMID: 39696994 PMCID: PMC11732766 DOI: 10.4285/ctr.24.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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Setyoboedi B, Utomo MT, Prihaningtyas RA, Arief S. Effectiveness of oral methylprednisolone as adjuvant therapy for clinical improvement, biochemical markers, and inflammation in infants with cholestasis. Heliyon 2024; 10:e34110. [PMID: 39113947 PMCID: PMC11305196 DOI: 10.1016/j.heliyon.2024.e34110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 08/10/2024] Open
Abstract
Aims This study analyzed the effectiveness of methylprednisolone in improving jaundice, bilirubin levels, liver function tests, and inflammatory biomarkers in infants with cholestasis. Methods The randomized, actively controlled, parallel-group trial (ISRCTN45080388 registry) was conducted from November 2022 to May 2023 in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia, on infants with cholestasis. The ethics committee of Dr. Soetomo General Academic Hospital, Surabaya approved the study protocol. Infants 14 days to 3 months old, with cholestasis followed by acholic stool, dark urine, and hepatomegaly were included in the trial. Participants were randomly assigned to methylprednisolone 2 mg/kg/day twice daily or to placebo twice daily for two weeks. Ursodeoxycholic acid (10 mg/kg) was administered to all patients thrice daily. Clinical examination and laboratory measurements (direct and total bilirubin, Aspartate aminotransferase (AST), Alanine transaminase (ALT), Gamma-glutamyl transferase (GGT), and inflammatory biomarker) were performed at baseline and after 2-week treatment. Measurement of inflammatory biomarkers (IL-2, IL-4, IL-6, IL-10, IFN-γ, TGF-β, and ANCA) was performed using enzyme-linked immunoassays. Data distribution was checked for normality. Analysis was carried out using SPSS ver. 21 with p significant <0.05. Results In total, 40 participants were randomized to methylprednisolone (n = 20; mean age 8.39 ± 3.11 weeks) and placebo (n = 18; 2 drop out; mean age 8.98 ± 2.80 weeks) groups. At baseline, the methylprednisolone treatment and placebo groups significantly differed in gender (p = 0.02) but not in clinical, laboratory examination, or inflammatory biomarker levels. The methylprednisolone group had direct bilirubin 8.36 ± 4.84 mg/dL; total bilirubin 10.40 (2.70-33.25) mg/dL; AST 187.05 (42.00-911.00) U/L; ALT 170.43 ± 134.43 U/L; IL-2 171.29 (73.70-378.57) ng/L; IL-4 119.57 ± 59.69 ng/L; IL-6 71.74 ± 29.83 ng/L; IL-10 138.15 ± 70.62 ng/L; IFN-γ 42.54 ± 12.17 ng/L; TGF-β 316.58 (163.68-606.16) ng/L; ANCA 1.70 (0.66-3.25) ng/L. After two weeks of treatment, direct bilirubin, total bilirubin, AST, IL-10, and IFN-γ levels were significantly lower in the methylprednisolone group (p < 0.05) than those in the placebo group. No serious adverse events were reported. Conclusion Methylprednisolone was efficacious in reducing 2-week bilirubin levels. These results support the hypothesis that the immunological process is involved in cholestasis. Further studies with larger sample sizes are needed to confirm the bile duct anti-inflammatory effect of methylprednisolone in cholestasis as an opportunity for new therapies to prevent the immunopathological process of cholestasis to biliary atresia.
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Affiliation(s)
- Bagus Setyoboedi
- Department of Child Health, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Department of Child Health, Faculty of Medicine - UNIVERSITAS AIRLANGGA, Surabaya, Indonesia
| | - Martono Tri Utomo
- Department of Child Health, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Department of Child Health, Faculty of Medicine - UNIVERSITAS AIRLANGGA, Surabaya, Indonesia
| | - Rendi Aji Prihaningtyas
- Department of Child Health, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Department of Child Health, Faculty of Medicine - UNIVERSITAS AIRLANGGA, Surabaya, Indonesia
| | - Sjamsul Arief
- Department of Child Health, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Department of Child Health, Faculty of Medicine - UNIVERSITAS AIRLANGGA, Surabaya, Indonesia
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Xiang L, An Z, Wu X, Wang J, Cai S, Lu Y, Li L, Huang W, Wu D, Lu L, Shi S, Bi H, Kou X. Carbon Dot-Loaded Apoptotic Vesicles Improve the Liver Kupffer Cell-Mediated Antibacterial Effect to Synergistically Alleviate Sepsis. ACS NANO 2024; 18:16726-16742. [PMID: 38888383 DOI: 10.1021/acsnano.4c01780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
Sepsis is a lethal systemic inflammatory disease against infection that lacks effective therapeutic approaches. Liver resident macrophage Kupffer cell (KC)-initiated bacterial clearance is crucial for the host to defend against infection. However, it remains unclear whether this process also governs the antibacterial therapy of sepsis that would be used to improve therapeutic outcomes. Here, we found that copper-doped carbon dots (Cu-CDs) exhibited superior antibacterial capabilities in vitro but displayed limited therapeutic effects in septic mice due to their limited ability to target the liver and restore KC antimicrobial capacity. Thus, we developed a composite nanodrug of copper-doped carbon dot-loaded apoVs (CC-apoVs) that combined the antibacterial ability of Cu-CDs and liver KC targeting features of apoV. Moreover, intravenous injection of CC-apoVs markedly alleviated the systemic infection and decreased the mortality of septic mice compared to Cu-CD and apoV infusion alone. Mechanistically, CC-apoV injection rescued impaired liver KCs during sepsis and enhanced their ability to capture and kill bloodborne bacteria. In addition, apoV-promoted macrophage killing of bacteria could be blocked by the inhibition of small GTPase Rab5. This study reveals a liver KC-targeted therapeutic strategy for sepsis and provides a nanodrug CC-apoV to improve the host antibacterial defense and amplify the therapeutic effect of the nanodrug.
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Affiliation(s)
- Lei Xiang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Zhe An
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Xiaoyan Wu
- School of Materials Science and Engineering, Anhui University, Hefei 230601, China
| | - Jinyang Wang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Simin Cai
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Yongxi Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Longchuang Li
- School of Materials Science and Engineering, Anhui University, Hefei 230601, China
| | - Weiying Huang
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Di Wu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Lu Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Songtao Shi
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Hong Bi
- School of Materials Science and Engineering, Anhui University, Hefei 230601, China
| | - Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
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Grayck MR, McCarthy WC, Solar M, Balasubramaniyan N, Zheng L, Orlicky DJ, Wright CJ. Implications of neonatal absence of innate immune mediated NFκB/AP1 signaling in the murine liver. Pediatr Res 2024; 95:1791-1802. [PMID: 38396130 DOI: 10.1038/s41390-024-03071-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/03/2024] [Accepted: 01/20/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown. METHODS Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes. RESULTS We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors. CONCLUSIONS These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury. IMPACT Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period. In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity. We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.
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Affiliation(s)
- Maya R Grayck
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - William C McCarthy
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mack Solar
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Natarajan Balasubramaniyan
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Lijun Zheng
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
| | - David J Orlicky
- Dept of Pathology, University of Colorado Anschutz School of Medicine, Aurora, CO, USA
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
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Akbulut Z, Aru B, Aydın F, Yanıkkaya Demirel G. Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Front Immunol 2024; 15:1379622. [PMID: 38638433 PMCID: PMC11024234 DOI: 10.3389/fimmu.2024.1379622] [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: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/20/2024] Open
Abstract
Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.
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Affiliation(s)
- Zeynep Akbulut
- Cancer and Stem Cell Research Center, Maltepe University, Istanbul, Türkiye
- Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, Istanbul, Türkiye
| | - Başak Aru
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
| | - Furkan Aydın
- Department of Immunology, Faculty of Medicine, Yeditepe University, Istanbul, Türkiye
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Choi B, Vu HT, Vu HT, Radwanska M, Magez S. Advances in the Immunology of the Host-Parasite Interactions in African Trypanosomosis, including Single-Cell Transcriptomics. Pathogens 2024; 13:188. [PMID: 38535532 PMCID: PMC10975194 DOI: 10.3390/pathogens13030188] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/11/2025] Open
Abstract
Trypanosomes are single-celled extracellular parasites that infect mammals, including humans and livestock, causing global public health concerns and economic losses. These parasites cycle between insect vectors, such as tsetse flies and vertebrate hosts, undergoing morphological, cellular, and biochemical changes. They have remarkable immune evasion mechanisms to escape the host's innate and adaptive immune responses, such as surface coat antigenic variation and the induction of the loss of specificity and memory of antibody responses, enabling the prolongation of infection. Since trypanosomes circulate through the host body in blood and lymph fluid and invade various organs, understanding the interaction between trypanosomes and tissue niches is essential. Here, we present an up-to-date overview of host-parasite interactions and survival strategies for trypanosomes by introducing and discussing the latest studies investigating the transcriptomics of parasites according to life cycle stages, as well as host cells in various tissues and organs, using single-cell and spatial sequencing applications. In recent years, this information has improved our understanding of trypanosomosis by deciphering the diverse populations of parasites in the developmental process, as well as the highly heterogeneous immune and tissue-resident cells involved in anti-trypanosome responses. Ultimately, the goal of these approaches is to gain an in-depth understanding of parasite biology and host immunity, potentially leading to new vaccination and therapeutic strategies against trypanosomosis.
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Affiliation(s)
- Boyoon Choi
- Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon 21985, Republic of Korea; (B.C.); (H.T.V.); (H.T.V.); (M.R.)
- Brussels Center for Immunology (BCIM), Department of Bioengineering Sciences (DBIT), Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium
- Department of Biochemistry and Microbiology WE10, Ghent University, 9000 Ghent, Belgium
| | - Hien Thi Vu
- Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon 21985, Republic of Korea; (B.C.); (H.T.V.); (H.T.V.); (M.R.)
- Department of Biomedical Molecular Biology WE14, Ghent University, 9052 Ghent, Belgium
| | - Hai Thi Vu
- Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon 21985, Republic of Korea; (B.C.); (H.T.V.); (H.T.V.); (M.R.)
- Department of Biomedical Molecular Biology WE14, Ghent University, 9052 Ghent, Belgium
| | - Magdalena Radwanska
- Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon 21985, Republic of Korea; (B.C.); (H.T.V.); (H.T.V.); (M.R.)
- Department of Biomedical Molecular Biology WE14, Ghent University, 9052 Ghent, Belgium
| | - Stefan Magez
- Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon 21985, Republic of Korea; (B.C.); (H.T.V.); (H.T.V.); (M.R.)
- Brussels Center for Immunology (BCIM), Department of Bioengineering Sciences (DBIT), Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium
- Department of Biochemistry and Microbiology WE10, Ghent University, 9000 Ghent, Belgium
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Pagano S, Bakker SJL, Juillard C, Vossio S, Moreau D, Brandt KJ, Mach F, Dullaart RPF, Vuilleumier N. Antibody against apolipoprotein-A1, non-alcoholic fatty liver disease and cardiovascular risk: a translational study. J Transl Med 2023; 21:694. [PMID: 37798764 PMCID: PMC10552329 DOI: 10.1186/s12967-023-04569-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/23/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common liver disease increasing cardiovascular disease (CVD) morbidity and mortality. Autoantibodies against apolipoprotein A-1 (AAA-1) are a possible novel CVD risk factor promoting inflammation and disrupting cellular lipid homeostasis, two prominent pathogenic features of NAFLD. We explored the role of AAA-1 in NAFLD and their association with CVD risk. METHODS HepaRG cells and liver sections from ApoE-/- mice exposed to AAA-1 were used for lipid quantification and conditional protein expression. Randomly selected sera from 312 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND) general population cohort were used to measure AAA-1. A Fatty Liver Index (FLI) ≥ 60 and a 10-year Framingham Risk Score (FRS) ≥ 20% were used as proxy of NAFLD and high CVD risk, respectively. RESULTS In-vitro and mouse models showed that AAA-1 increased triglyceride synthesis leading to steatosis, and promoted inflammation and hepatocyte injury. In the 112 PREVEND participants with FLI ≥ 60, AAA-1 were associated with higher FRS, alkaline phosphatase levels, lower HDL cholesterol and tended to display higher FLI values. Univariate linear and logistic regression analyses (LRA) confirmed significant associations between AAA-1, FLI and FRS ≥ 20%, while in adjusted LRA, FLI was the sole independent predictor of FRS ≥ 20% (OR: 1.05, 95%CI 1.01-1.09, P = 0.003). AAA-1 was not an independent FLI predictor. CONCLUSIONS AAA-1 induce a NAFLD-compatible phenotype in vitro and in mice. Intricate associations exist between AAA-1, CVD risk and FLI in the general population. Further work is required to refine the role of AAA-1 in NAFLD and to determine if the AAA-1 association with CVD is affected by hepatic steatosis.
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Affiliation(s)
- Sabrina Pagano
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Rue Michel Servet 1, 1211, Geneva, Switzerland.
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland.
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Catherine Juillard
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland
| | - Stefania Vossio
- School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Dimitri Moreau
- School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Karim J Brandt
- Department of Cardiology, University Hospitals of Geneva, Geneva, Switzerland
| | - François Mach
- Department of Cardiology, University Hospitals of Geneva, Geneva, Switzerland
| | - Robin P F Dullaart
- Department of Internal Medicine, Division of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, Rue Michel Servet 1, 1211, Geneva, Switzerland
- Department of Medicine Specialties, Medical Faculty, Geneva University, Geneva, Switzerland
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10
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Meena NK, Randazzo D, Raben N, Puertollano R. AAV-mediated delivery of secreted acid α-glucosidase with enhanced uptake corrects neuromuscular pathology in Pompe mice. JCI Insight 2023; 8:e170199. [PMID: 37463048 PMCID: PMC10543735 DOI: 10.1172/jci.insight.170199] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 07/11/2023] [Indexed: 08/23/2023] Open
Abstract
Gene therapy is under advanced clinical development for several lysosomal storage disorders. Pompe disease, a debilitating neuromuscular illness affecting infants, children, and adults with different severity, is caused by a deficiency of lysosomal glycogen-degrading enzyme acid α-glucosidase (GAA). Here, we demonstrated that adeno-associated virus-mediated (AAV-mediated) systemic gene transfer reversed glycogen storage in all key therapeutic targets - skeletal and cardiac muscles, the diaphragm, and the central nervous system - in both young and severely affected old Gaa-knockout mice. Furthermore, the therapy reversed secondary cellular abnormalities in skeletal muscle, such as those in autophagy and mTORC1/AMPK signaling. We used an AAV9 vector encoding a chimeric human GAA protein with enhanced uptake and secretion to facilitate efficient spread of the expressed protein among multiple target tissues. These results lay the groundwork for a future clinical development strategy in Pompe disease.
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Affiliation(s)
- Naresh K. Meena
- Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Davide Randazzo
- Light Imaging Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA
| | - Nina Raben
- Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Rosa Puertollano
- Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
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11
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Ma S, Lv M, Chen X, Zang G, Tang Z, Zhang Y, Hu W. Avasimibe can cooperate with a DC-targeting and integration-deficient lentivector to induce stronger HBV specific T cytotoxic response by regulating cholesterol metabolism. Antiviral Res 2023; 216:105662. [PMID: 37393054 DOI: 10.1016/j.antiviral.2023.105662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/25/2023] [Accepted: 06/29/2023] [Indexed: 07/03/2023]
Abstract
We have reported a lentivector which could effectively induce HBV-specific cytotoxic T lymphocytes (CTLs). Avasimibe is an inhibitor of acetyl-CoA acetyltransferase-1 (ACAT1), and has been shown to enhance T lymphocyte cytotoxicity on tumor cells. However, the role of avasimibe in lentivector-induced HBV-specific T cytotoxic response remains unknown. Based on previous study, we constructed an integration-deficient lentivector LVDC-ID-HBV (harboring HBcAg expression), and the in vitro experiments showed that the combination of avasimibe exhibited better efficacy in inducing HBV-specific CTL responses including cell proliferation, production of cytokines, as well as CTL killing activities. Mechanism experiments showed that increasing cell membrane cholesterol levels by MβCD-coated cholesterol or ACAT1 inhibition efficiently promoted TCR clustering, signaling transduction and immunological synapse formation, thereby mediating augmented CTL responses. Nevertheless, the depletion of plasma membrane cholesterol with MβCD led to obviously decreased CTL responses. The avasimibe-mediated strengthened immune effects were also determined in animal experiments and the results were in agreement with those from the in vitro research. In particular, the in vivo CTL killing activities were identified by the CFSE or BV-labeled splenocyte lysis assay. Moreover, the experiments in HBV transgenic mice showed that the LVDC-ID-HBV plus avasimibe group demonstrated the lowest serum HBsAg and HBV DNA levels, as well as the lowest expression of HBsAg and HBcAg in liver tissues. We concluded that the HBV-specific CTL immune responses could be potentiated by avasimibe through regulating plasma membrane cholesterol levels. Avasimibe may be a potential adjuvant for lentivector vaccine against HBV infection.
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Affiliation(s)
- Siyuan Ma
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Mengjiao Lv
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xiaohua Chen
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Guoqing Zang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zhenghao Tang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yi Zhang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Weiwei Hu
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
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12
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Yahoo N, Dudek M, Knolle P, Heikenwälder M. Role of immune responses for development of NAFLD-associated liver cancer and prospects for therapeutic modulation. J Hepatol 2023:S0168-8278(23)00165-4. [PMID: 36893854 DOI: 10.1016/j.jhep.2023.02.033] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 02/04/2023] [Accepted: 02/14/2023] [Indexed: 03/11/2023]
Abstract
The liver is the central metabolic organ of the body regulating energy and lipid metabolism and at the same time has potent immunological functions. Overwhelming the metabolic capacity of the liver by obesity and sedentary lifestyle leads to hepatic lipid accumulation, chronic necro-inflammation, enhanced mitochondrial/ER-stress and development of non-alcoholic fatty liver disease (NAFLD), with its pathologic form nonalcoholic steatohepatitis (NASH). Based on knowledge on pathophysiological mechanisms, specifically targeting metabolic diseases to prevent or slow down progression of NAFLD to liver cancer will become possible. Genetic/environmental factors contribute to development of NASH and liver cancer progression. The complex pathophysiology of NAFLD-NASH is reflected by environmental factors, particularly the gut microbiome and its metabolic products. NAFLD-associated HCC occurs in most of the cases in the context of a chronically inflamed liver and cirrhosis. Recognition of environmental alarmins or metabolites derived from the gut microbiota and the metabolically injured liver create a strong inflammatory milieu supported by innate and adaptive immunity. Several recent studies indicate that the chronic hepatic microenvironment of steatosis induces auto-aggressive CD8+CXCR6+PD1+ T cells secreting TNF and upregulating FasL to eliminate parenchymal and non-parenchymal cells in an antigen independent manner. This promotes chronic liver damage and a pro-tumorigenic environment. CD8+CXCR6+PD1+ T cells possess an exhausted, hyperactivated, resident phenotype and trigger NASH to HCC transition, and might be responsible for a less efficient treatment response to immune-check-point inhibitors - in particular atezolizumab/bevacizumab. Here, we provide an overview of NASH-related inflammation/pathogenesis focusing on new discoveries on the role of T cells in NASH-immunopathology and therapy response. This review discusses preventive measures to halt disease progression to liver cancer and therapeutic strategies to manage NASH-HCC patients.
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Affiliation(s)
- Neda Yahoo
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Michael Dudek
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Percy Knolle
- Institute of Molecular Immunology and Experimental Oncology, School of Medicine, Technical University of Munich (TUM), Munich, Germany.
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; The M3 Research Institute, Karl Eberhards Universitaet Tübingen, Medizinische Fakultät, Otfried-Müller-Straße 37, 72076 Tübingen.
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13
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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14
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Trevisan B, Rodriguez M, Medder H, Lankford S, Combs R, Owen J, Atala A, Porada CD, Almeida-Porada G. Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels. Front Immunol 2022; 13:1070476. [PMID: 36532079 PMCID: PMC9755880 DOI: 10.3389/fimmu.2022.1070476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/21/2022] [Indexed: 12/04/2022] Open
Abstract
Introduction Hemophilia A (HA) is the most common X-linked bleeding disorder, occurring in 1 in 5,000 live male births and affecting >1 million individuals worldwide. Although advances in protein-based HA therapeutics have improved health outcomes, current standard-of-care requires infusion 2-3 times per week for life, and 30% of patients develop inhibitors, significantly increasing morbidity and mortality. There are thus unmet medical needs requiring novel approaches to treat HA. Methods We tested, in a highly translational large animal (sheep) model, whether the unique immunological and biological properties of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) could enable them to serve as cellular delivery vehicles to provide long-term expression of FVIII, avoiding the need for frequent infusions. Results We show that autologous BM-MSCs can be isolated, transduced with a lentivector to produce high levels of ovine (o)FVIII, extensively expanded, and transplanted into adult animals safely. The transplanted cells engraft in multiple organs, and they stably produce and secrete sufficient quantities of FVIII to yield elevated plasma FVIII levels for at least 15 weeks. Discussion These studies thus highlight the promise of cellular-based gene delivery approaches for treating HA.
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Affiliation(s)
- Brady Trevisan
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Martin Rodriguez
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Hailey Medder
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Shannon Lankford
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Rebecca Combs
- Special Hematology Laboratory, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - John Owen
- Special Hematology Laboratory, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Christopher D. Porada
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Fetal Research and Therapy Program, Wake Forest School of Medicine, Winston-Salem, NC, United States,*Correspondence: Graça Almeida-Porada,
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15
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Li J, Diamante G, Ahn IS, Wijaya D, Wang X, Chang CH, Ha SM, Immadisetty K, Meng H, Nel A, Yang X, Xia T. Determination of the nanoparticle- and cell-specific toxicological mechanisms in 3D liver spheroids using scRNAseq analysis. NANO TODAY 2022; 47:101652. [PMID: 36911538 PMCID: PMC10004129 DOI: 10.1016/j.nantod.2022.101652] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Engineered nanomaterials (ENMs) are commonly used in consumer products, allowing exposure to target organs such as the lung, liver, and skin that could lead to adverse health effects in humans. To better reflect on toxicological effects in liver cells, it is important to consider the contribution of hepatocyte morphology, function, and intercellular interactions in a dynamic 3D microenvironment. Herein, we used a 3D liver spheroid model containing hepatocyte and Kupffer cells (KCs) to study the effects of three different material compositions, namely vanadium pentoxide (V2O5), titanium dioxide (TiO2), or graphene oxide (GO). Additionally, we used single-cell RNA sequencing (scRNAseq) to determine the nanoparticle (NP) and cell-specific toxicological responses. A general finding was that hepatocytes exhibit more variation in gene expression and adaptation of signaling pathways than KCs. TNF-α production tied to the NF-κB pathway was a commonly affected pathway by all NPs while impacts on the metabolic function of hepatocytes were unique to V2O5. V2O5 NPs also showed the largest number of differentially expressed genes in both cell types, many of which are related to pro-inflammatory and apoptotic response pathways. There was also evidence of mitochondrial ROS generation and caspase-1 activation after GO and V2O5 treatment, in association with cytokine production. All considered, this study provides insight into the impact of nanoparticles on gene responses in key liver cell types, providing us with a scRNAseq platform that can be used for high-content screening of nanomaterial impact on the liver, for use in biosafety and biomedical applications.
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Affiliation(s)
- Jiulong Li
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Graciel Diamante
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - In Sook Ahn
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Darren Wijaya
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Xiang Wang
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Chong Hyun Chang
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Sung-min Ha
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Kavya Immadisetty
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Huan Meng
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
| | - André Nel
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Xia Yang
- Molecular Toxicology Interdepartmental Program, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
- Department of Integrative Biology and Physiology, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA
| | - Tian Xia
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA
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16
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Shen W, Chen Y, Lei P, Sheldon M, Sun Y, Yao F, Ma L. Immunotherapeutic Approaches for Treating Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:5013. [PMID: 36291797 PMCID: PMC9599666 DOI: 10.3390/cancers14205013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Liver cancer is a life-threatening disease, and its incidence is increasing globally. The most common form of liver cancer is hepatocellular carcinoma (HCC). Approximately half of patients with HCC, especially those at advanced disease stages, receive systemic therapies, including the tyrosine kinase inhibitors sorafenib and lenvatinib. Over the past few years, immune checkpoint inhibitors (ICIs) have changed the landscape of HCC treatment. In particular, the combination therapy with atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) significantly improved survival benefits compared with sorafenib as a single agent, a finding that has stimulated further preclinical and clinical development of immunotherapeutic approaches for treating HCC. In addition to ICIs, oncolytic immunotherapy and adoptive T cell therapy have also emerged as immunotherapeutic strategies. A major challenge is that the tumor microenvironment of HCC is usually immunosuppressive, leading to immune escape and immunotherapy resistance. Hence, combination therapies that could sensitize HCC to immunotherapy have become a growing area of investigation. In this review, we summarize recent advances in HCC immuno-oncology and review immunotherapeutic strategies that are under development for treating HCC.
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Affiliation(s)
- Wanying Shen
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
| | - Yujie Chen
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
| | - Pan Lei
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Marisela Sheldon
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan 430070, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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17
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Reiner G. Entzündungs- und Nekrosesyndrom des Schweins (SINS) – eine Übersicht. Tierarztl Prax Ausg G Grosstiere Nutztiere 2022; 50:323-332. [DOI: 10.1055/a-1950-7975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
ZusammenfassungEntzündungen und Teilverluste des Schwanzes treten in hoher Frequenz auf und müssen bekämpft werden, wenn das Tierwohl beim Schwein verbessert werden soll. Dabei greift die alleinige Berücksichtigung des Schwanzbeißens zu kurz. Entzündungen und Nekrosen des Schwanzes treten regelmäßig auch ohne Zutun anderer Schweine auf. Der Nachweis entsprechender Veränderungen bereits zum Zeitpunkt der Geburt, das gehäuft synchrone Auftreten an so verschiedenen Körperlokalisationen wie Schwanz, Ohren, Zitzen, Klauen und anderen Partien, sowie der pathohistologische Nachweis Blutgefäß-assoziierter Veränderungen sprechen für eine primär endogene Ursache und ein Syndrom, auch wenn die Symptomatik mit Umweltfaktoren interagiert. Die Veränderungen können bei Saug- und Absatzferkeln sowie in der Mast beobachtet werden. Die Verbesserung der Umwelt kann zu erheblicher Reduktion von Entzündungen und Nekrosen führen. Gleichzeitig zeigen sich erhebliche genetische Effekte der Eber und Sauen. Der vorliegende Übersichtsartikel beleuchtet alle bislang bekannten Facetten von SINS (Swine Inflammation and Necrosis Syndrome) und gibt einen Einblick in die Eckpunkte der Pathogenese. Das Bewusstsein für ein neues und vom Schwanzbeißen abzugrenzendes Krankheitsbild soll einen Beitrag zu dessen Bekämpfung und somit zur Steigerung des Tierwohls beim Schwein leisten.
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Affiliation(s)
- Gerald Reiner
- Klinikum Veterinärmedizin, Justus-Liebig-Universität Gießen
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18
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Zhang S, Lu S, Li Z. Extrahepatic factors in hepatic immune regulation. Front Immunol 2022; 13:941721. [PMID: 36052075 PMCID: PMC9427192 DOI: 10.3389/fimmu.2022.941721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver via both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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19
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Sun X, Wu J, Liu L, Chen Y, Tang Y, Liu S, Chen H, Jiang Y, Liu Y, Yuan H, Lu Y, Chen Z, Cai J. Transcriptional switch of hepatocytes initiates macrophage recruitment and T-cell suppression in endotoxemia. J Hepatol 2022; 77:436-452. [PMID: 35276271 DOI: 10.1016/j.jhep.2022.02.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 02/06/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The liver plays crucial roles in the regulation of immune defense during acute systemic infections. However, the roles of liver cellular clusters and intercellular communication in the progression of endotoxemia have not been well-characterized. METHODS Single-cell RNA sequencing analysis was performed, and the transcriptomes of 19,795 single liver cells from healthy and endotoxic mice were profiled. The spatial and temporal changes in hepatocytes and non-parenchymal cell types were validated by multiplex immunofluorescence staining, bulk transcriptomic sequencing, or flow cytometry. Furthermore, we used an adeno-associated virus delivery system to confirm the major mechanisms mediating myeloid cell infiltration and T-cell suppression in septic murine liver. RESULTS We identified a proinflammatory hepatocyte (PIH) subpopulation that developed primarily from periportal hepatocytes and to a lesser extent from pericentral hepatocytes and played key immunoregulatory roles in endotoxemia. Multicellular cluster modeling of ligand-receptor interactions revealed that PIHs play a crucial role in the recruitment of macrophages via the CCL2-CCR2 interaction. Recruited macrophages (RMs) released cytokines (e.g., IL6, TNFα, and IL17) to induce the expression of inhibitory ligands, such as PD-L1, on hepatocytes. Subsequently, RM-stimulated hepatocytes led to the suppression of CD4+ and memory T-cell subsets partly via the PD-1/PD-L1 interaction in endotoxemia. Furthermore, sinusoidal endothelial cells expressed the highest levels of proapoptotic and inflammatory genes around the periportal zone. This pattern of gene expression facilitated increases in the number of fenestrations and infiltration of immune cells in the periportal zone. CONCLUSIONS Our study elucidates unanticipated aspects of the cellular and molecular effects of endotoxemia on liver cells at the single-cell level and provides a conceptual framework for the development of novel therapeutic approaches for acute infection. LAY SUMMARY The liver plays a crucial role in the regulation of immune defense during acute systemic infections. We identified a proinflammatory hepatocyte subpopulation and demonstrated that the interactions of this subpopulation with recruited macrophages are pivotal in the immune response during endotoxemia. These novel findings provide a conceptual framework for the discovery of rational therapeutic targets in acute infection.
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Affiliation(s)
- Xuejing Sun
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Junru Wu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Lun Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Chen
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yan Tang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Suzhen Liu
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China
| | - Youxiang Jiang
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yuanyuan Liu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Hong Yuan
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yao Lu
- The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Zhaoyang Chen
- Department of Cardiology, Fujian Medical Center for Cardiovascular Diseases, Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China.
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; The Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
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20
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Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages. Acta Pharmacol Sin 2022; 43:2016-2025. [PMID: 35022542 PMCID: PMC9343373 DOI: 10.1038/s41401-021-00842-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023]
Abstract
Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 μM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 μM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.
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21
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Wang J, Zhang L, Shi Q, Yang B, He Q, Wang J, Weng Q. Targeting innate immune responses to attenuate acetaminophen-induced hepatotoxicity. Biochem Pharmacol 2022; 202:115142. [PMID: 35700755 DOI: 10.1016/j.bcp.2022.115142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/02/2022]
Abstract
Acetaminophen (APAP) hepatotoxicity is an important cause of acute liver failure, resulting in massive deaths in many developed countries. Currently, the metabolic process of APAP in the body has been well studied. However, the underlying mechanism of APAP-induced liver injury remains elusive. Increasing clinical and experimental evidences indicate that the innate immune responses are involved in the pathogenesis of APAP-induced acute liver injury (AILI), in which immune cells have dual roles of inducing inflammation to exacerbate hepatotoxicity and removing dead cells and debris to help liver regeneration. In this review, we summarize the latest findings of innate immune cells involved in AILI, particularly emphasizing the activation of innate immune cells and their different roles during the injury and repair phases. Moreover, current available treatments are discussed according to the different roles of innate immune cells in the development of AILI. This review aims to update the knowledge about innate immune responses in the pathogenesis of AILI, and provide potential therapeutic interventions for AILI.
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Affiliation(s)
- Jincheng Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Lulu Zhang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qi Shi
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bo Yang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jiajia Wang
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Qinjie Weng
- Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
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22
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Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2022; 54:598-613. [PMID: 34344577 DOI: 10.1016/j.dld.2021.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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23
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Casey LM, Hughes KR, Saunders MN, Miller SD, Pearson RM, Shea LD. Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance. Biomaterials 2022; 283:121457. [PMID: 35286851 PMCID: PMC11225973 DOI: 10.1016/j.biomaterials.2022.121457] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/10/2022] [Accepted: 03/03/2022] [Indexed: 02/06/2023]
Abstract
The intravenous delivery of disease-relevant antigens (Ag) by polymeric nanoparticles (NP-Ags) has demonstrated Ag-specific immune tolerance in autoimmune and allergic disorders as well as allogeneic transplant rejection. NP-Ags are observed to distribute to the spleen, which has an established role in the induction of immune tolerance. However, studies have shown that the spleen is dispensable for NP-Ag-induced tolerance, suggesting significant contributions from other immunological sites. Here, we investigated the tolerogenic contributions of Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) to NP-Ag-induced tolerance in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Intravenously delivered Ag-conjugated poly(lactide-co-glycolide) NPs (PLG-Ag) distributed largely to the liver, where they associated with both KCs and LSECs. This distribution was accompanied by CD4 T cell accumulation, clonal deletion, and PD-L1 expression by KCs and LSECs. Ex vivo co-cultures of PLG-Ag-treated KCs or LSECs with Ag-specific CD4 T cells resulted in PGE2 and IL-10 or PGE2 secretion, respectively. KC depletion and adoptive transfer experiments demonstrated that KCs were sufficient, but not necessary, to mediate PLG-Ag-induced tolerance in EAE. The durability of PLG-Ag-induced tolerance in the absence of KCs may be attributed to the distribution of PLG-Ags to LSECs, which demonstrated similar levels of PD-L1, PGE2, and T cell stimulatory ability. Collectively, these studies provide mechanistic support for the role of liver KCs and LSECs in Ag-specific tolerance for a biomaterial platform that is currently being evaluated in clinical trials.
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Affiliation(s)
- Liam M Casey
- Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA
| | - Kevin R Hughes
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109, USA
| | - Michael N Saunders
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109, USA; Medical Scientist Training Program, University of Michigan, 1135 Catherine St., 2965 Taubman Health Sciences Library, Ann Arbor, MI, 48109, USA
| | - Stephen D Miller
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 6-713 Tarry Building, 303 E. Chicago Avenue, Chicago, IL, 60611, USA; Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA; The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA
| | - Ryan M Pearson
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine Street, Baltimore, MD, 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, Baltimore, MD, 21201, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201, USA.
| | - Lonnie D Shea
- Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109, USA.
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24
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Li J, Chen C, Xia T. Understanding Nanomaterial-Liver Interactions to Facilitate the Development of Safer Nanoapplications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2106456. [PMID: 35029313 PMCID: PMC9040585 DOI: 10.1002/adma.202106456] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/23/2021] [Indexed: 05/02/2023]
Abstract
Nanomaterials (NMs) are widely used in commercial and medical products, such as cosmetics, vaccines, and drug carriers. Exposure to NMs via various routes such as dermal, inhalation, and ingestion has been shown to gain access to the systemic circulation, resulting in the accumulation of NMs in the liver. The unique organ structures and blood flow features facilitate the liver sequestration of NMs, which may cause adverse effects in the liver. Currently, most in vivo studies are focused on NMs accumulation at the organ level and evaluation of the gross changes in liver structure and functions, however, cell-type-specific uptake and responses, as well as the molecular mechanisms at cellular levels leading to effects at organ levels are lagging. Herein, the authors systematically review diverse interactions of NMs with the liver, specifically on major liver cell types including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes as well as the detailed molecular mechanisms involved. In addition, the knowledge gained on nano-liver interactions that can facilitate the development of safer nanoproducts and nanomedicine is also reviewed.
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Affiliation(s)
- Jiulong Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Chunying Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Tian Xia
- Center of Environmental Implications of Nanotechnology (UC CEIN), California NanoSystems Institute, Division of NanoMedicine, Department of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
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25
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The Bright and the Dark Side of TGF-β Signaling in Hepatocellular Carcinoma: Mechanisms, Dysregulation, and Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14040940. [PMID: 35205692 PMCID: PMC8870127 DOI: 10.3390/cancers14040940] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/02/2022] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Transforming growth factor β (TGF-β) signaling is a preeminent regulator of diverse cellular and physiological processes. Frequent dysregulation of TGF-β signaling has been implicated in cancer. In hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, the autocrine and paracrine effects of TGF-β have paradoxical implications. While acting as a potent tumor suppressor pathway in the early stages of malignancy, TGF-β diverts to a promoter of tumor progression in the late stages, reflecting its bright and dark natures, respectively. Within this context, targeting TGF-β represents a promising therapeutic option for HCC treatment. We discuss here the molecular properties of TGF-β signaling in HCC, attempting to provide an overview of its effects on tumor cells and the stroma. We also seek to evaluate the dysregulation mechanisms that mediate the functional switch of TGF-β from a tumor suppressor to a pro-tumorigenic signal. Finally, we reconcile its biphasic nature with the therapeutic implications. Abstract Hepatocellular carcinoma (HCC) is associated with genetic and nongenetic aberrations that impact multiple genes and pathways, including the frequently dysregulated transforming growth factor β (TGF-β) signaling pathway. The regulatory cytokine TGF-β and its signaling effectors govern a broad spectrum of spatiotemporally regulated molecular and cellular responses, yet paradoxically have dual and opposing roles in HCC progression. In the early stages of tumorigenesis, TGF-β signaling enforces profound tumor-suppressive effects, primarily by inducing cell cycle arrest, cellular senescence, autophagy, and apoptosis. However, as the tumor advances in malignant progression, TGF-β functionally switches to a pro-tumorigenic signal, eliciting aggressive tumor traits, such as epithelial–mesenchymal transition, tumor microenvironment remodeling, and immune evasion of cancer cells. On this account, the inhibition of TGF-β signaling is recognized as a promising therapeutic strategy for advanced HCC. In this review, we evaluate the functions and mechanisms of TGF-β signaling and relate its complex and pleiotropic biology to HCC pathophysiology, attempting to provide a detailed perspective on the molecular determinants underlying its functional diversion. We also address the therapeutic implications of the dichotomous nature of TGF-β signaling and highlight the rationale for targeting this pathway for HCC treatment, alone or in combination with other agents.
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26
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Werner M, Schefczyk S, Trippler M, Treckmann JW, Baba HA, Gerken G, Schlaak JF, Broering R. Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses 2022; 14:218. [PMID: 35215812 PMCID: PMC8874605 DOI: 10.3390/v14020218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
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Affiliation(s)
- Melanie Werner
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Juergen W. Treckmann
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Hideo A. Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Straße 2, 42549 Velbert, Germany
| | - Joerg F. Schlaak
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- AMEOS Hospital, St. Clemens, Internal Medicine—Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
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27
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Liu M, Zhang H, Zhang L, Liu X, Zhou S, Wang X, Zhong W, Zhang J, Wang B, Zhao J, Zhou L. RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism. Int J Biol Sci 2022; 18:199-213. [PMID: 34975327 PMCID: PMC8692153 DOI: 10.7150/ijbs.65402] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/16/2021] [Indexed: 12/13/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.
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Affiliation(s)
- Man Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.,Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Hongxia Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Lu Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Simin Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Xiaoyi Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.,Department of Gastroenterology and Hepatology, People's Hospital of Hetian District, Xinjiang Uygur Autonomous Region, China
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Kong H, Ju E, Yi K, Xu W, Lao Y, Cheng D, Zhang Q, Tao Y, Li M, Ding J. Advanced Nanotheranostics of CRISPR/Cas for Viral Hepatitis and Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2102051. [PMID: 34665528 PMCID: PMC8693080 DOI: 10.1002/advs.202102051] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/25/2021] [Indexed: 05/08/2023]
Abstract
Liver disease, particularly viral hepatitis and hepatocellular carcinoma (HCC), is a global healthcare burden and leads to more than 2 million deaths per year worldwide. Despite some success in diagnosis and vaccine development, there are still unmet needs to improve diagnostics and therapeutics for viral hepatitis and HCC. The emerging clustered regularly interspaced short palindromic repeat/associated proteins (CRISPR/Cas) technology may open up a unique avenue to tackle these two diseases at the genetic level in a precise manner. Especially, liver is a more accessible organ over others from the delivery point of view, and many advanced strategies applied for nanotheranostics can be adapted in CRISPR-mediated diagnostics or liver gene editing. In this review, the focus is on these two aspects of viral hepatitis and HCC applications. An overview on CRISPR editor development and current progress in clinical trials is first given, followed by highlighting the recent advances integrating the merits of gene editing and nanotheranostics. The promising systems that are used in other applications but may hold potentials in liver gene editing are also discussed. This review concludes with the perspectives on rationally designing the next-generation CRISPR approaches and improving the editing performance.
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Affiliation(s)
- Huimin Kong
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
| | - Enguo Ju
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
| | - Ke Yi
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
| | - Weiguo Xu
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
| | - Yeh‐Hsing Lao
- Department of Biomedical EngineeringColumbia University3960 Broadway Lasker Room 450New YorkNY10032USA
| | - Du Cheng
- PCFM Lab of Ministry of EducationSchool of Materials Science and EngineeringSun Yat‐sen University135 Xingangxi RoadGuangzhou510275P. R. China
| | - Qi Zhang
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
- Guangdong Provincial Key Laboratory of Liver Disease Research600 Tianhe RoadGuangzhou510630P. R. China
| | - Yu Tao
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
- Guangdong Provincial Key Laboratory of Liver Disease Research600 Tianhe RoadGuangzhou510630P. R. China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational MedicineCenter for Nanomedicine and Biotherapy CenterThe Third Affiliated HospitalSun Yat‐sen University600 Tianhe RoadGuangzhou510630P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
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González-Silvera D, Cuesta A, Esteban MÁ. Immune defence mechanisms presented in liver homogenates and bile of gilthead seabream (Sparus aurata). JOURNAL OF FISH BIOLOGY 2021; 99:1958-1967. [PMID: 34486119 DOI: 10.1111/jfb.14901] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 08/23/2021] [Accepted: 08/31/2021] [Indexed: 06/13/2023]
Abstract
Because the role of the liver of fishes in providing possible immunity remains largely unknown, the aim of this work was to identify and characterize different humoral defence mechanisms in the liver homogenates and bile of gilthead seabream (Sparus aurata) for the first time. Total protein levels and several immune parameters (complement activity, lysozyme and immunoglobulin M level) were studied. Furthermore, the activity of some lytic (proteases, antiproteases, esterase, alkaline phosphatase) and antioxidant (superoxide dismutase, catalase and peroxidase) enzymes was determined. Finally, bacteriostatic activity on three opportunist fish pathogens (Vibrio harveyi, Vibrio angillarum and Photobacterium damselae) was measured. Lysozyme and antiprotease activity were undetected in liver and bile, while natural haemolytic complement activity was only detected in bile, and immunoglobulin M was detected in both samples. The levels of proteases, esterase and antioxidant enzymes were greater in bile than in liver homogenates, while the level of alkaline phosphatase was very low in both samples. In addition, while no bacteriostatic activity was detected on liver homogenates, the bile revealed a very potent bacteriostatic activity against all the tested pathogenic bacteria. These results corroborate that fish liver - especially fish bile - contains many factors involved in innate immunity that could be useful for better understanding the role of the liver as an organ involved in fish immune functions as well as the possible contribution of bile to gut mucosal immunity.
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Affiliation(s)
- Daniel González-Silvera
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Murcia, Spain
| | - Alberto Cuesta
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Murcia, Spain
| | - Maria Ángeles Esteban
- Immunobiology for Aquaculture Group, Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, Murcia, Spain
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30
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Yamaguchi M, Dohi N, Ooka A, Saito SY, Ishikawa T. Caffeine-induced inversion of prostaglandin E 2 effects on hepatic stellate cell activation. Biomed Pharmacother 2021; 142:111989. [PMID: 34388524 DOI: 10.1016/j.biopha.2021.111989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS Liver inflammation leads to the activation of hepatic stellate cells (HSCs), resulting in the development of liver fibrosis. The present study aimed to investigate the effects of prostaglandin E2 (PGE2), which is biosynthesized by Kupffer cells, hepatocytes, and HSCs during inflammation, on HSC activation, including its combinatory effect with caffeine. METHODS HSCs isolated from mice were activated by culturing in a medium supplemented with 10% fetal bovine serum for 7 days on plastic plates. The activation of HSCs was evaluated by immunofluorescence of α-smooth muscle actin in HSCs. Comprehensive gene expression analysis was performed using mRNA-sequencing to compare HSCs cultured for 1 or 7 days, with or without PGE2, caffeine, or both. RESULTS PGE2 (1 μM) facilitated the activation of HSCs but inhibited the HSC activation in the presence of caffeine (3 mM). Comprehensive gene expression analysis revealed that HSCs treated with PGE2 in the presence of caffeine were classified in the same class as HSCs cultured for 1 day, i.e., quiescent HSCs. In contrast, PGE2 did not exhibit an inhibitory effect on HSC activation when co-treated with any isoform-specific phosphodiesterase inhibitors. Although the adenylate cyclase inhibitor 2',5'-dideoxyadenosine suppressed the elevation of intracellular cAMP level induced by PGE2 in the presence of caffeine, it had no effect on the inhibition of HSC activation by PGE2 plus caffeine. CONCLUSION The effect of PGE2 on HSC activation is changed from facilitatory to inhibitory when combined with caffeine, suggesting that caffeine may effectively suppress liver fibrosis during inflammation.
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Affiliation(s)
- Momoka Yamaguchi
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan.
| | - Naoki Dohi
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Akira Ooka
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan
| | - Shin-Ya Saito
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan; Faculty of Veterinary Medicine, Okayama University of Science, 1-3 Ikoinooka, Imabari City, Ehime 794-8555, Japan
| | - Tomohisa Ishikawa
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526, Japan
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31
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Lee J, Kim SR, Lee C, Jun YI, Bae S, Yoon YJ, Kim OY, Gho YS. Extracellular vesicles from in vivo liver tissue accelerate recovery of liver necrosis induced by carbon tetrachloride. J Extracell Vesicles 2021; 10:e12133. [PMID: 34401049 PMCID: PMC8357636 DOI: 10.1002/jev2.12133] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/19/2021] [Accepted: 07/27/2021] [Indexed: 01/07/2023] Open
Abstract
Extracellular vesicles (EVs) are nano-sized vesicles composed of proteolipid bilayers carrying various molecular signatures of the cells. As mediators of intercellular communications, EVs have gained great attention as new therapeutic agents in the field of nanomedicine. Therefore, many studies have explored the roles of cell-derived EVs isolated from cultured hepatocytes or stem cells as inducer of liver proliferation and regeneration under various pathological circumstances. However, study investigating the role of EVs directly isolated from liver tissue has not been performed. Herein, to understand the pathophysiological role and to investigate the therapeutic potential of in vivo liver EVs, we isolated EVs from both normal and carbon tetrachloride (CCl4)-induced damaged in vivo liver tissues. The in vivo EVs purified from liver tissues display typical features of EVs including spherical morphology, nano-size, and enrichment of tetraspanins. Interestingly, administration of both normal and damaged liver EVs significantly accelerated the recovery of liver tissue from CCl4-induced hepatic necrosis. This restorative action was through the induction of hepatocyte growth factor at the site of the injury. These results suggest that not only normal liver EVs but also damaged liver EVs play important pathophysiological roles of maintaining homeostasis after tissue damage. Our study, therefore, provides new insight into potentially developing in vivo EV-based therapeutics for preventing and treating liver diseases.
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Affiliation(s)
- Jaemin Lee
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Sae Rom Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Changjin Lee
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Ye In Jun
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Seoyoon Bae
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
| | - Yae Jin Yoon
- Genome Editing Research CentreKorea Research Institute of Bioscience and BiotechnologyDaejeonRepublic of Korea
| | - Oh Youn Kim
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
- Department of MedicineYonsei University College of MedicineSeoulRepublic of Korea
| | - Yong Song Gho
- Department of Life SciencesPohang University of Science and Technology (POSTECH)PohangRepublic of Korea
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Dänicke S, Heymann AK, Oster M, Wimmers K, Tesch T, Bannert E, Bühler S, Kersten S, Frahm J, Kluess J, Kahlert S, Rothkötter HJ, Billenkamp F. Does chronic dietary exposure to the mycotoxin deoxynivalenol affect the porcine hepatic transcriptome when an acute-phase response is initiated through first or second-pass LPS challenge of the liver? Innate Immun 2021; 27:388-408. [PMID: 34338001 PMCID: PMC8419296 DOI: 10.1177/17534259211030563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The sensitivity of pigs to deoxynivalenol (DON) might be increased by systemic inflammation (SI), which also has consequences for hepatic integrity. Liver lesions and a dys-regulated gene network might hamper hepatic handling and elimination of DON whereby the way of initiation of hepatic inflammation might play an additional role. First and second-pass exposure of the liver with LPS for triggering a SI was achieved by LPS infusion via pre- or post-hepatic venous route, respectively. Each infusion group was pre-conditioned either with a control diet (0.12 mg DON/kg diet) or with a DON-contaminated diet (4.59 mg DON/kg diet) for 4 wk. Liver transcriptome was evaluated at 195 min after starting infusions. DON exposure alone failed to modulate the mRNA expression significantly. However, pre- and post-hepatic LPS challenges prompted transcriptional responses in immune and metabolic levels. The mRNAs for B-cell lymphoma 2-like protein 11 as a key factor in apoptosis and IFN-γ released by T cells were clearly up-regulated in DON-fed group infused with LPS post-hepatically. On the other hand, mRNAs for nucleotide binding oligomerization domain containing 2, IFN-α and eukaryotic translation initiation factor 2α kinase 3 as ribosomal stress sensors were exclusively up-regulated in control pigs with pre-hepatic LPS infusion. These diverse effects were traced back to differences in TLR4 signalling.
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Affiliation(s)
- Sven Dänicke
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Ann-Katrin Heymann
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Michael Oster
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Germany
| | - Klaus Wimmers
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Germany
| | - Tanja Tesch
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Erik Bannert
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Susanne Bühler
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Susanne Kersten
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Jana Frahm
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Jeannette Kluess
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
| | - Stefan Kahlert
- Institute of Anatomy, Otto-von-Guericke University Magdeburg, Germany
| | | | - Fabian Billenkamp
- Institute of Animal Nutrition, Federal Research Institute for Animal Health, Friedrich-Loeffler-Institut, Germany
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Benedicto A, García-Kamiruaga I, Arteta B. Neuropilin-1: A feasible link between liver pathologies and COVID-19. World J Gastroenterol 2021; 27:3516-3529. [PMID: 34239266 PMCID: PMC8240058 DOI: 10.3748/wjg.v27.i24.3516] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/16/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a tremendous impact on the health of millions of people worldwide. Unfortunately, those suffering from previous pathological conditions are more vulnerable and tend to develop more severe disease upon infection with the new SARS-CoV-2. This coronavirus interacts with the angiotensin-converting enzyme 2 receptor to invade the cells. Recently, another receptor, neuropilin-1 (NRP-1), has been reported to amplify the viral infection. Interestingly, NRP-1 is expressed in nonparenchymal liver cells and is related to and upregulated in a wide variety of liver-related pathologies. It has been observed that SARS-CoV-2 infection promotes liver injury through several pathways that may be influenced by the previous pathological status of the patient and liver expression of NRP-1. Moreover, coronavirus disease 2019 causes an inflammatory cascade called cytokine storm in patients with severe disease. This cytokine storm may influence liver sinusoidal-cell phenotype, facilitating viral invasion. In this review, the shreds of evidence linking NRP-1 with liver pathologies such as hepatocellular carcinoma, liver fibrosis, nonalcoholic fatty liver disease and inflammatory disorders are discussed in the context of SARS-CoV-2 infection. In addition, the involvement of the infection-related cytokine storm in NRP-1 overexpression and the subsequent increased risk of SARS-CoV-2 infection are also analyzed. This review aims to shed some light on the involvement of liver NRP-1 during SARS-CoV-2 infection and emphasizes the possible involvement this receptor with the observed liver damage.
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Affiliation(s)
- Aitor Benedicto
- Department of Cellular Biology and Histology, School of Medicine and Nursing, University of the Basque Country, Leioa 48940, Bizkaia, Spain
| | - Iñigo García-Kamiruaga
- Department of Gastroenterology and Hepatology, San Eloy Hospital, Barakaldo 48902, Spain
| | - Beatriz Arteta
- Department of Cellular Biology and Histology, School of Medicine and Nursing, University of the Basque Country, Leioa 48940, Bizkaia, Spain
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Reiner G, Kuehling J, Loewenstein F, Lechner M, Becker S. Swine Inflammation and Necrosis Syndrome (SINS). Animals (Basel) 2021; 11:1670. [PMID: 34205208 PMCID: PMC8228460 DOI: 10.3390/ani11061670] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 01/03/2023] Open
Abstract
Tail biting is a prevalent and undesirable behaviour in pigs and a major source of significant reduction in well-being. However, focusing on biting considers only one part of the solution, because tail damage can be found with a high prevalence without any action by other pigs. The lesions are not limited to the tail but can also be found in the ears, heels, soles, claw coronary bands, teats, navel, vulva, and face. Environmental improvement alone often fails to overcome the problem. This review addresses a new inflammation and necrosis syndrome in swine (SINS). It shows the clinical signs and the frequencies of occurrence in different age groups. It compiles scientific evidence from clinical and histopathological studies in newborn piglets that argue for a primary endogenous aetiology of the disease. Bringing together the findings of a broad body of research, the possible mechanisms leading to the disease are identified and then discussed. This part will especially focus on microbe-associated molecular patterns in the circulation and their role in activating defence mechanisms and inflammation. Finally, the methods are identified to ameliorate the problem by optimizing husbandry and selecting a suitable breeding stock.
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Grants
- 123 Tönnies Forschung, Rheda, Germany
- 456 Ministerium für Umwelt, Klimaschutz, Landwirtschaft und Verbraucherschutz, Hessen, Germa-ny
- 789 Ministerium für Umwelt, Klima, Landwirtschaft und Verbraucherschutz, Nordrhein-Westfalen, Germany.
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Affiliation(s)
- Gerald Reiner
- Department of Veterinary Clinical Sciences, Clinic for Swine, Justus Liebig University Giessen, Frankfurter Strasse 112, 35392 Giessen, Germany; (J.K.); (S.B.)
| | - Josef Kuehling
- Department of Veterinary Clinical Sciences, Clinic for Swine, Justus Liebig University Giessen, Frankfurter Strasse 112, 35392 Giessen, Germany; (J.K.); (S.B.)
| | | | | | - Sabrina Becker
- Department of Veterinary Clinical Sciences, Clinic for Swine, Justus Liebig University Giessen, Frankfurter Strasse 112, 35392 Giessen, Germany; (J.K.); (S.B.)
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Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
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Li J, Guiney LM, Downing JR, Wang X, Chang CH, Jiang J, Liu Q, Liu X, Mei KC, Liao YP, Ma T, Meng H, Hersam MC, Nel AE, Xia T. Dissolution of 2D Molybdenum Disulfide Generates Differential Toxicity among Liver Cell Types Compared to Non-Toxic 2D Boron Nitride Effects. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101084. [PMID: 34032006 PMCID: PMC8225588 DOI: 10.1002/smll.202101084] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/18/2021] [Indexed: 05/07/2023]
Abstract
2D boron nitride (BN) and molybdenum disulfide (MoS2 ) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS2 could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS2 , dispersed in Pluronic F87 (designated BN-PF and MoS2 -PF) is compared with aggregated forms of these materials (BN-Agg and MoS2 -Agg) in liver cells. MoS2 induces dose-dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non-toxic. The effect of MoS2 could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7-mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS2 -Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase-1 activation, IL-1β, and IL-18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS2 in impacting KC viability.
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Affiliation(s)
- Jiulong Li
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Linda M Guiney
- Departments of Materials Science and Engineering Chemistry and Medicine, Northwestern University, Evanston, IL, 60208, USA
| | - Julia R Downing
- Departments of Materials Science and Engineering Chemistry and Medicine, Northwestern University, Evanston, IL, 60208, USA
| | - Xiang Wang
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
- Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Chong Hyun Chang
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Jinhong Jiang
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Qi Liu
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Xiangsheng Liu
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Kuo-Ching Mei
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Yu-Pei Liao
- Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Tiancong Ma
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
| | - Huan Meng
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
- Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Mark C Hersam
- Departments of Materials Science and Engineering Chemistry and Medicine, Northwestern University, Evanston, IL, 60208, USA
| | - André E Nel
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
- Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Tian Xia
- Center of Environmental Implications of Nanotechnology (UC CEIN), California Nanosystems Institute, University of California, Los Angeles, CA, 90095, USA
- Division of Nanomedicine, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
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Haas G, Fan S, Ghadimi M, De Oliveira T, Conradi LC. Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases. Front Cell Dev Biol 2021; 9:612774. [PMID: 33912554 PMCID: PMC8072376 DOI: 10.3389/fcell.2021.612774] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.
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Affiliation(s)
- Gwendolyn Haas
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Shuang Fan
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago De Oliveira
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
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Guo W, Zhou X, Li X, Zhu Q, Peng J, Zhu B, Zheng X, Lu Y, Yang D, Wang B, Wang J. Depletion of Gut Microbiota Impairs Gut Barrier Function and Antiviral Immune Defense in the Liver. Front Immunol 2021; 12:636803. [PMID: 33841420 PMCID: PMC8027085 DOI: 10.3389/fimmu.2021.636803] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.
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Affiliation(s)
- Weina Guo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zhou
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoran Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingfeng Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Peng
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinping Lu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baoju Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junzhong Wang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhang Y, Hill GE, Ge Z, Park NR, Taylor HA, Andreasen V, Tardy L, Kavazis AN, Bonneaud C, Hood WR. Effects of a Bacterial Infection on Mitochondrial Function and Oxidative Stress in a Songbird. Physiol Biochem Zool 2021; 94:71-82. [PMID: 33399516 DOI: 10.1086/712639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
AbstractAs a major physiological mechanism involved in cellular renewal and repair, immune function is vital to the body's capacity to support tissue maintenance and organismal survival. Because immune defenses can be energetically expensive, the activities of metabolically active organs, such as the liver, are predicted to increase during infection by most pathogens. However, some pathogens are immunosuppressive, which might reduce the metabolic capacities of select organs to suppress immune response. Mycoplasma gallisepticum (MG) is a well-known immunosuppressive bacterium that infects domestic chickens and turkeys as well as songbirds. In the house finch (Haemorhous mexicanus), which is the primary host for MG among songbird species, MG infects both the respiratory system and the conjunctiva of the eye, causing conspicuous swelling. To study the effect of a systemic bacterial infection on cellular respiration and oxidative damage in the house finch, we measured mitochondrial respiration, mitochondrial membrane potential, reactive oxygen species production, and oxidative damage in the livers of house finches that were wild caught and either infected with MG, as indicated by genetic screening for the pathogen, or free of MG infection. We observed that MG-infected house finches showed significantly lower oxidative lipid and protein damage in liver tissue compared with their uninfected counterparts. Moreover, using complex II substrates, we documented a nonsignificant trend for lower state 3 respiration of liver mitochondria in MG-infected house finches compared with uninfected house finches (P=0.07). These results are consistent with the hypothesis that MG suppresses organ function in susceptible hosts.
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Rao T, Liu YT, Zeng XC, Li CP, Ou-Yang DS. The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury. Acta Pharmacol Sin 2021; 42:27-35. [PMID: 32123300 PMCID: PMC7921551 DOI: 10.1038/s41401-020-0360-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023]
Abstract
Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.
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Affiliation(s)
- Tai Rao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, China.
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China.
| | - Ya-Ting Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Xiang-Chang Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China
| | - Chao-Peng Li
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, 410205, China
| | - Dong-Sheng Ou-Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical Pharmacology, Central South University, Changsha, 410008, China.
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008, China.
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, 410205, China.
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Bhandari S, Li R, Simón-Santamaría J, McCourt P, Johansen SD, Smedsrød B, Martinez-Zubiaurre I, Sørensen KK. Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages. BMC Mol Cell Biol 2020; 21:85. [PMID: 33246411 PMCID: PMC7694354 DOI: 10.1186/s12860-020-00331-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body's most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics. RESULTS We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. CONCLUSIONS Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.
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Affiliation(s)
- Sabin Bhandari
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Ruomei Li
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Jaione Simón-Santamaría
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Peter McCourt
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
| | - Steinar Daae Johansen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.,Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Bård Smedsrød
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway.
| | | | - Karen Kristine Sørensen
- Department of Medical Biology, Vascular Biology Research Group, University of Tromsø (UiT) -The Arctic University of Norway, Hansine Hansens veg 18, N-9037, Tromsø, Norway
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42
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Dänicke S, Bannert E, Tesch T, Kersten S, Frahm J, Bühler S, Sauerwein H, Görs S, Kahlert S, Rothkötter HJ, Metges CC, Kluess J. Oral exposure of pigs to the mycotoxin deoxynivalenol does not modulate the hepatic albumin synthesis during a LPS-induced acute-phase reaction. Innate Immun 2020; 26:716-732. [PMID: 32703050 PMCID: PMC7787558 DOI: 10.1177/1753425920937778] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The sensitivity of pigs to deoxynivalenol (DON) might be influenced by systemic
inflammation (SI) which impacts liver. Besides following acute-phase proteins,
our aim was to investigate both the hepatic fractional albumin (ALB) synthesis
rate (FSR) and the ALB concentration as indicators of ALB metabolism in presence
and absence of SI induced by LPS via pre- or post-hepatic venous route. Each
infusion group was pre-conditioned either with a control diet (CON, 0.12 mg
DON/kg diet) or with a DON-contaminated diet (DON, 4.59 mg DON/kg diet) for 4
wk. A depression of ALB FSR was observed 195 min after LPS challenge,
independent of feeding group or LPS application route, which was not paralleled
by a down-regulated ALB mRNA expression but by a reduced availability of free
cysteine. The drop in ALB FSR only partly explained the plasma ALB
concentrations which were more depressed in the DON-pre-exposed groups,
suggesting that ALB levels are influenced by further mechanisms. The abundances
of haptoglobin, C-reactive protein, serum amyloid A, pig major acute-phase
protein, fibrinogen and LPS-binding protein mRNA were up-regulated upon LPS
stimulation but not accompanied by increases in the plasma concentrations of
these proteins, pointing at an imbalance between synthesis and consumption.
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Affiliation(s)
- Sven Dänicke
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Erik Bannert
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Tanja Tesch
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Susanne Kersten
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Jana Frahm
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Susanne Bühler
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
| | - Helga Sauerwein
- Institute for Animal Science, Physiology and Hygiene, University of Bonn, Bonn, Germany
| | - Solvig Görs
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Stefan Kahlert
- Institute of Anatomy, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | | | - Cornelia C Metges
- Institute of Nutritional Physiology "Oskar Kellner", Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany
| | - Jeannette Kluess
- Institute of Animal Nutrition, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Braunschweig, Germany
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Jiang Y, Que W, Zhu P, Li XK. The Role of Diverse Liver Cells in Liver Transplantation Tolerance. Front Immunol 2020; 11:1203. [PMID: 32595648 PMCID: PMC7304488 DOI: 10.3389/fimmu.2020.01203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.
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Affiliation(s)
- Yanzhi Jiang
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Weitao Que
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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44
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Immunological Basis of Genesis of Hepatocellular Carcinoma: Unique Challenges and Potential Opportunities through Immunomodulation. Vaccines (Basel) 2020; 8:vaccines8020247. [PMID: 32456200 PMCID: PMC7349974 DOI: 10.3390/vaccines8020247] [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: 04/24/2020] [Revised: 05/16/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
A majority of hepatocellular carcinoma (HCC) develops in the setting of persistent chronic inflammation as immunological mechanisms have been shown to play a vital role in the initiation, growth and progression of tumours. The index review has been intended to highlight ongoing immunological changes in the hepatic parenchyma responsible for the genesis and progression of HCC. The in-situ vaccine effect of radiofrequency (RF) is through generation tumour-associated antigens (TAAs), following necrosis and apoptosis of tumour cells, which not only re-activates the antitumour immune response but can also act in synergism with checkpoint inhibitors to generate a superlative effect with intent to treat primary cancer and distant metastasis. An improved understanding of oncogenic responses of immune cells and their integration into signaling pathways of the tumour microenvironment will help in modulating the antitumour immune response. Finally, we analyzed contemporary literature and summarised the recent advances made in the field of targeted immunotherapy involving checkpoint inhibitors along with RF application with the intent to reinstate antitumour immunity and outline future directives in very early and early stages of HCC.
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45
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Piechnik M, Sawamoto K, Ohnishi H, Kawamoto N, Ago Y, Tomatsu S. Evading the AAV Immune Response in Mucopolysaccharidoses. Int J Mol Sci 2020; 21:E3433. [PMID: 32414007 PMCID: PMC7279460 DOI: 10.3390/ijms21103433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/31/2022] Open
Abstract
The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of glycosaminoglycan (GAG)-degrading enzymes essential for the treatment of MPS. Patients who have antibodies against AAV capsid increase in number with age, serotype, and racial background and are excluded from the clinical trials at present. In addition, patients who have undergone AAV gene therapy are often excluded from the additional AAV gene therapy with the same serotype, since their acquired immune response (antibody) against AAV will limit further efficacy of treatment. Several methods are being developed to overcome this immune response, such as novel serotype design, antibody reduction by plasmapheresis and immunosuppression, and antibody evasion using empty capsids and enveloped AAV vectors. In this review, we examine the mechanisms of the anti-AAV humoral immune response and evaluate the strengths and weaknesses of current evasion strategies in order to provide an evidence-based recommendation on evading the immune response for future AAV-mediated gene therapies for MPS.
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Affiliation(s)
- Matthew Piechnik
- Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; (M.P.); (K.S.)
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA
| | - Kazuki Sawamoto
- Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; (M.P.); (K.S.)
| | - Hidenori Ohnishi
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan; (H.O.); (N.K.); (Y.A.)
| | - Norio Kawamoto
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan; (H.O.); (N.K.); (Y.A.)
| | - Yasuhiko Ago
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan; (H.O.); (N.K.); (Y.A.)
| | - Shunji Tomatsu
- Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; (M.P.); (K.S.)
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan; (H.O.); (N.K.); (Y.A.)
- Department of Pediatrics, Shimane University, Shimane 690-8504, Japan
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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46
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Sandhu N, Navarro V. Drug-Induced Liver Injury in GI Practice. Hepatol Commun 2020; 4:631-645. [PMID: 32363315 PMCID: PMC7193133 DOI: 10.1002/hep4.1503] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 02/18/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
Although drug-induced liver injury (DILI) is a rare clinical event, it carries significant morbidity and mortality, leaving it as the leading cause of acute liver failure in the United States. It is one of the most challenging diagnoses encountered by gastroenterologists. The development of various drug injury networks has played a vital role in expanding our knowledge regarding drug-related and herbal and dietary supplement-related liver injury. In this review, we discuss what defines liver injury, epidemiology of DILI, its biochemical and pathologic patterns, and management.
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Affiliation(s)
- Naemat Sandhu
- Division of Digestive Diseases and TransplantationAlbert Einstein Healthcare NetworkPhiladelphiaPA
| | - Victor Navarro
- Division of Digestive Diseases and TransplantationAlbert Einstein Healthcare NetworkPhiladelphiaPA
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47
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Recent Advances in Immunotherapy for Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12040775. [PMID: 32218257 PMCID: PMC7226090 DOI: 10.3390/cancers12040775] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 03/22/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.
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48
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Li F, Huang G, Tan F, Yi R, Zhou X, Mu J, Zhao X. Lactobacillus plantarum KSFY06 on d-galactose-induced oxidation and aging in Kunming mice. Food Sci Nutr 2020; 8:379-389. [PMID: 31993164 PMCID: PMC6977475 DOI: 10.1002/fsn3.1318] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/30/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022] Open
Abstract
Yogurt from Xinjiang, China, is a traditional Chinese fermented food rich in beneficial microorganisms, such as Lactobacillus plantarum KSFY06. In this study, the effect of KSFY06 on oxidative aging was investigated using live animal experiments. Molecular biological methods were used to analyze the serum and tissues of mice with oxidative aging induced by d-galactose, which showed that KSFY06 can inhibit the decline of heart, liver, spleen, and kidney caused by aging. The KSFY06 strain increased the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and glutathione (GSH) in serum and liver of aging mice, while the content of malondialdehyde (MDA) is reduced. Pathological observation showed that KSFY06 alleviated damage to the liver, spleen, and skin of oxidative aging mice. qPCR showed that, at high dose (2 × 109 cfu/kg per day), KSFY06 upregulates copper/zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), catalase (CAT) mRNA expression, and its downstream inducible nitric oxide synthase (iNOS) mRNA expression in liver and spleen tissues induced by d-gal. To a certain extent, these findings indicate that L. plantarum KSFY06 is able to protect against oxidative stress in the d-gal-induced aging model. In conclusion, L. plantarum KSFY06 may provide a potential research value in the prevention or alleviation of related diseases caused by oxidative stress.
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Affiliation(s)
- Fang Li
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
- College of Biological and Chemical EngineeringChongqing University of EducationChongqingChina
| | - Guangbin Huang
- Department of Trauma SurgeryEmergency Medical Center of ChongqingThe Affiliated Central Hospital of Chongqing UniversityChongqingChina
| | - Fang Tan
- Department of Public HealthOur Lady of Fatima UniversityValenzuelaPhilippines
| | - Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
| | - Xianrong Zhou
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
| | - Jianfei Mu
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Research Center of Functional FoodChongqing University of EducationChongqingChina
- Chongqing Engineering Laboratory for Research and Development of Functional FoodChongqing University of EducationChongqingChina
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Ali SE, Waddington JC, Park BK, Meng X. Definition of the Chemical and Immunological Signals Involved in Drug-Induced Liver Injury. Chem Res Toxicol 2019; 33:61-76. [PMID: 31682113 DOI: 10.1021/acs.chemrestox.9b00275] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Idiosyncratic drug-induced liver injury (iDILI), which is rare and often recognized only late in drug development, poses a major public health concern and impediment to drug development due to its high rate of morbidity and mortality. The mechanisms of DILI are not completely understood; both non-immune- and immune-mediated mechanisms have been proposed. Non-immune-mediated mechanisms including direct damage to hepatocytes, mitochondrial toxicity, interference with transporters, and alteration of bile ducts are well-known to be associated with drugs such as acetaminophen and diclofenac; whereas immune-mediated mechanisms involving activation of both adaptive and innate immune cells and the interactions of these cells with parenchymal cells have been proposed. The chemical signals involved in activation of both innate and adaptive immune responses are discussed with respect to recent scientific advances. In addition, the immunological signals including cytokine and chemokines that are involved in promoting liver injury are also reviewed. Finally, we discuss how liver tolerance and regeneration can have profound impact on the pathogenesis of iDILI. Continuous research in developing in vitro systems incorporating immune cells with liver cells and animal models with impaired liver tolerance will provide an opportunity for improved prediction and prevention of immune-mediated iDILI.
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Affiliation(s)
- Serat-E Ali
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - James C Waddington
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
| | - Xiaoli Meng
- MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology , University of Liverpool , Liverpool L69 3GE , United Kingdom
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Affiliation(s)
- Chiara Gabbi
- University of Modena and Reggio Emilia, Modena, Italy
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