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1
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Ou LL, Jiang JL, Guo ML, Wu JH, Zhong WW, He YH. Research progress on the roles of complement in liver injury. World J Hepatol 2025; 17:103839. [PMID: 40177195 PMCID: PMC11959660 DOI: 10.4254/wjh.v17.i3.103839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/29/2025] [Accepted: 02/27/2025] [Indexed: 03/26/2025] Open
Abstract
The complement system is crucial for maintaining immunological homeostasis in the liver, playing a significant role in both innate and adaptive immune responses. Dysregulation of this system is closely linked to the pathogenesis of various liver diseases. Modulating the complement system can affect the progression of these conditions. To provide insights into treating liver injury by targeting the regulation of the complement system, we conducted a comprehensive search of major biomedical databases, including MEDLINE, PubMed, EMBASE, and Web of Science, to identify articles on complement and liver injury and reviewed the functions and mechanisms of the complement system in liver injury.
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Affiliation(s)
- Li-Li Ou
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Lian Jiang
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Man-Lu Guo
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Jin-Hua Wu
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Wei-Wei Zhong
- Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China
| | - Yi-Huai He
- Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China.
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Yu SMW, King E, Fribourg M, Hartzell S, Tsou L, Gee L, D'Agati VD, Thurman JM, He JC, Cravedi P. A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:126-142. [PMID: 39427763 PMCID: PMC11686444 DOI: 10.1016/j.ajpath.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/03/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024]
Abstract
Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/-, myeloid cell-specific, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1-/- RTECs. Moreover, C5ar1-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1-/- mice in AAN and FAN. These data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, thereby revealing a novel link between the complement system and tubular cell metabolism.
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Affiliation(s)
- Samuel Mon-Wei Yu
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York.
| | - Emily King
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Miguel Fribourg
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Susan Hartzell
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Liam Tsou
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Logan Gee
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University, New York, New York
| | - Joshua M Thurman
- Medicine-Renal Med Diseases/Hypertension, Colorado University, Aurora, Colorado
| | - John Cijiang He
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York; James J. Peters Department of Veterans Affairs Medical Center, New York, New York
| | - Paolo Cravedi
- Nephrology Division, Department of Medicine, Mount Sinai Hospital, New York, New York.
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Li Y, Horst K, Greven J, Mert Ü, Lupu L, Palmer A, Doerfer L, Zhao Q, Zhang X, Halbgebauer R, Ignatius A, Marzi I, van Griensven M, Balmayor E, Hildebrand F, Mollnes TE, Huber-Lang M. Modulation of the hepatic RANK-RANKL-OPG axis by combined C5 and CD14 inhibition in a long-term polytrauma model. Front Immunol 2024; 15:1434274. [PMID: 39640261 PMCID: PMC11617561 DOI: 10.3389/fimmu.2024.1434274] [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: 05/17/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024] Open
Abstract
Background Polytrauma and hemorrhagic shock can lead to direct and indirect liver damage involving intricate pathophysiologic mechanisms. While hepatic function has been frequently highlighted, there is minimal research on how the receptor activator of the NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is regulated in the liver following trauma. Furthermore, cross-talking complement and toll-like-receptor (TLR) systems can contribute to the posttraumatic response. Therefore, we investigated the hepatic consequences of polytrauma focusing on the RANK-RANKL-OPG axis, and evaluated the effects of a dual blockade of complement factor C5 and TLR-cofactor CD14 on hepatic features. Methods The established pig model of polytrauma (PT) and hemorrhagic shock included pulmonary contusion, hepatic dissection, and bilateral femur fractures, surgically addressed either by external fixation (Fix ex) or intramedullary nailing (Nail). Four groups were investigated: 1) sham animals; 2) PT treated by Fix ex (Fix ex); 3) PT by Nail (Nail); or 4) PT by Nail plus combined C5/CD14 inhibition (Nail+Therapy). Serum samples were obtained between 0 - 72 h, and liver samples at 72 h after PT. Liver tissues were histologically scored and subjected to RT-qPCR-analyses, immunohistochemistry and ELISAs to evaluate the posttraumatic hepatic response with a focus on the RANK-RANKL-OPG system. Results Following PT, the liver injury score of the Nail+Therapy group was significantly lower than in the Fix ex or Nail group without immunomodulation (p<0.05). Similarly, the degree of necrosis, lobular stasis, and inflammation were significantly reduced when treated with C5/CD14-inhibitors. Compared to the Nail group, AST serum concentrations were significantly decreased in the Nail+Therapy group after 72 h (p<0.05). PCR analyses indicated that RANK, RANKL, and OPG levels in the liver were increased after PT in the Nail group compared to lower levels in the Nail+Therapy group. Furthermore, liver tissue analyses revealed increased RANK protein levels and cellular immunostaining for RANK in the Nail group, both of which were significantly reduced in the case of C5/CD14-inhibition (p<0.05). Conclusion Following experimental PT, dual inhibition of C5/CD14 resulted in altered, mainly reduced hepatic synthesis of proteins relevant to bone repair. However, a comprehensive investigation of the subsequent effects on the liver-bone axis are needed.
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Affiliation(s)
- Yang Li
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Klemens Horst
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Johannes Greven
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Ümit Mert
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Ludmila Lupu
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Lena Doerfer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Qun Zhao
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Xing Zhang
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Ingo Marzi
- Department of Trauma, Hand, and Reconstructive Surgery, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany
| | - Martijn van Griensven
- The Department of Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands
| | - Elizabeth Balmayor
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Frank Hildebrand
- Department of Orthopaedics, Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany
| | - Tom Eirik Mollnes
- Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway
- Research Laboratory, Nordland Hospital Bodø, Bodø, Norway
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
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Huang J, Xu T, Quan G, Li Y, Yang X, Xie W. Current progress on the microbial therapies for acute liver failure. Front Microbiol 2024; 15:1452663. [PMID: 39479215 PMCID: PMC11521890 DOI: 10.3389/fmicb.2024.1452663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Acute liver failure (ALF), associated with a clinical fatality rate exceeding 80%, is characterized by severe liver damage resulting from various factors in the absence of pre-existing liver disease. The role of microbiota in the progression of diverse liver diseases, including ALF, has been increasingly recognized, with the interactions between the microbiota and the host significantly influencing both disease onset and progression. Despite growing interest in the microbiological aspects of ALF, comprehensive reviews remain limited. This review critically examines the mechanisms and efficacy of microbiota-based treatments for ALF, focusing on their role in prevention, treatment, and prognosis over the past decade.
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Affiliation(s)
- Jiayuan Huang
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Tianyu Xu
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Guoqiao Quan
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuange Li
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoya Yang
- Department of Physiology, Guangzhou Health Science College, Guangzhou, China
| | - Wenrui Xie
- Department of Gastroenterology, Research Center for Engineering Techniques of Microbiota-Targeted Therapies of Guangdong Province, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Mannes M, Savukoski S, Ignatius A, Halbgebauer R, Huber-Lang M. Crepuscular rays - The bright side of complement after tissue injury. Eur J Immunol 2024; 54:e2350848. [PMID: 38794857 DOI: 10.1002/eji.202350848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024]
Abstract
Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host-protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement-targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.
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Affiliation(s)
- Marco Mannes
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Susa Savukoski
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute for Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Ulm University Medical Center, Ulm, Germany
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Qi B, Li Y, Peng Z, Luo Z, Zhang X, Chen J, Li G, Sun Y. Macrophage-Myofibroblast Transition as a Potential Origin for Skeletal Muscle Fibrosis After Injury via Complement System Activation. J Inflamm Res 2024; 17:1083-1094. [PMID: 38384372 PMCID: PMC10880461 DOI: 10.2147/jir.s450599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 02/14/2024] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Acute skeletal muscle injury is common in sports. The injured muscle cannot fully recover due to fibrosis resulting from myofibroblasts. Understanding the origin of fibroblasts is, therefore, important for the development of anti-fibrotic therapies. Accumulating evidence shows that a mechanism called macrophage-myofibroblast transition (MMT) can lead to tissue or organ fibrosis, yet it is still unclear whether MMT exists in skeletal muscle and the exact mechanisms. METHODS Single-cell transcriptome of mice skeletal muscle after acute injury was analyzed with a specific attention on the process of MMT. Cell-cell interaction network, pseudotime trajectory analysis, Gene Ontology (GO), and Kyoto Genome Encyclopedia (KEGG) were conducted. A series of experiments in vivo and in vitro were launched for verification. RESULTS Single cell transcriptomic analysis indicated that, following acute injury, there were much interactions between macrophages and myofibroblasts. A detailed analysis on macrophages indicated that, CD68+α-SMA+ cells, which represented the status of MMT, mainly appeared at five days post-injury. KEGG/GO analysis underlined the involvement of complement system, within which C3ar1, C1qa, C1qb, and C1qc were up-regulated. Trajectory analysis also confirmed a potential shift from macrophages to myofibroblasts. These findings were verified by histological study in mice skeletal muscle, that there were much MMT cells at five days, declined gradually, and vanished 14 days after trauma, when there was remarkable fibrosis formation within the injured muscle. Moreover, C3a stimulation could directly induce MMT in BMDMs. CONCLUSION Fibrosis following acute injury is disastrous to skeletal muscle, but the origin of myofibroblasts remains unclear. We proved that, following acute injury, macrophage-myofibroblast transition happened in skeletal muscle, which may contribute to fibrosis formation. This phenomenon mainly occurred at five days post-injury. The complement system can activate MMT. More evidence is needed to directly support the pro-fibrotic role of MMT in skeletal muscle fibrosis after acute injury.
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Affiliation(s)
- Beijie Qi
- Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China
| | - Yuqi Li
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Zhen Peng
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xingyu Zhang
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Jiwu Chen
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Guoqi Li
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yaying Sun
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
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Maspero M, Yilmaz S, Cazzaniga B, Raj R, Ali K, Mazzaferro V, Schlegel A. The role of ischaemia-reperfusion injury and liver regeneration in hepatic tumour recurrence. JHEP Rep 2023; 5:100846. [PMID: 37771368 PMCID: PMC10523008 DOI: 10.1016/j.jhepr.2023.100846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 09/30/2023] Open
Abstract
The risk of cancer recurrence after liver surgery mainly depends on tumour biology, but preclinical and clinical evidence suggests that the degree of perioperative liver injury plays a role in creating a favourable microenvironment for tumour cell engraftment or proliferation of dormant micro-metastases. Understanding the contribution of perioperative liver injury to tumour recurrence is imperative, as these pathways are potentially actionable. In this review, we examine the key mechanisms of perioperative liver injury, which comprise mechanical handling and surgical stress, ischaemia-reperfusion injury, and parenchymal loss leading to liver regeneration. We explore how these processes can trigger downstream cascades leading to the activation of the immune system and the pro-inflammatory response, cellular proliferation, angiogenesis, anti-apoptotic signals, and release of circulating tumour cells. Finally, we discuss the novel therapies under investigation to decrease ischaemia-reperfusion injury and increase regeneration after liver surgery, including pharmaceutical agents, inflow modulation, and machine perfusion.
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Affiliation(s)
- Marianna Maspero
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
| | - Sumeyye Yilmaz
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Beatrice Cazzaniga
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Roma Raj
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Khaled Ali
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Vincenzo Mazzaferro
- General Surgery and Liver Transplantation Unit, IRCCS Istituto Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Italy
| | - Andrea Schlegel
- Transplantation Center, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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Farkona S, Pastrello C, Konvalinka A. Proteomics: Its Promise and Pitfalls in Shaping Precision Medicine in Solid Organ Transplantation. Transplantation 2023; 107:2126-2142. [PMID: 36808112 DOI: 10.1097/tp.0000000000004539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Solid organ transplantation is an established treatment of choice for end-stage organ failure. However, all transplant patients are at risk of developing complications, including allograft rejection and death. Histological analysis of graft biopsy is still the gold standard for evaluation of allograft injury, but it is an invasive procedure and prone to sampling errors. The past decade has seen an increased number of efforts to develop minimally invasive procedures for monitoring allograft injury. Despite the recent progress, limitations such as the complexity of proteomics-based technology, the lack of standardization, and the heterogeneity of populations that have been included in different studies have hindered proteomic tools from reaching clinical transplantation. This review focuses on the role of proteomics-based platforms in biomarker discovery and validation in solid organ transplantation. We also emphasize the value of biomarkers that provide potential mechanistic insights into the pathophysiology of allograft injury, dysfunction, or rejection. Additionally, we forecast that the growth of publicly available data sets, combined with computational methods that effectively integrate them, will facilitate a generation of more informed hypotheses for potential subsequent evaluation in preclinical and clinical studies. Finally, we illustrate the value of combining data sets through the integration of 2 independent data sets that pinpointed hub proteins in antibody-mediated rejection.
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Affiliation(s)
- Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Soham and Shaila Ajmera Family Transplant Centre, University Health Network, Toronto, ON, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Canadian Donation and Transplantation Research Program, Edmonton, AB, Canada
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Kong E, Li Y, Geng X, Wang J, He Y, Feng X. Ischemic preconditioning attenuates endoplasmic reticulum stress-dependent apoptosis of hepatocytes by regulating autophagy in hepatic ischemia-reperfusion injury. Int Immunopharmacol 2023; 122:110637. [PMID: 37473713 DOI: 10.1016/j.intimp.2023.110637] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 07/02/2023] [Accepted: 07/09/2023] [Indexed: 07/22/2023]
Abstract
Hepatic ischemia-reperfusion injury (HIRI) usually occurs during subtotal hepatectomy and severely damages liver function during the perioperative period. Endoplasmic reticulum stress (ERS) dependent apoptosis has been suggested to play a crucial role in HIRI progression. The present study focused on the regulatory effect of autophagy activation induced by ischemic preconditioning (IPC) on ERS-dependent apoptosis of hepatocytes in HIRI. A HIRI mouse model and oxygen-glucose deprivation/reperfusion (OGD/R) AML-12 hepatocyte cell lines were constructed to evaluate the protective effect of IPC in vivo and in vitro. The protein levels of p-eIF2α, CHOP, and cleaved caspase-12 were used to evaluate the ERS-dependent apoptosis, whereas LC3-II and p62 were considered as the autophagy activation markers. The beneficial molecular chaperones GRP78, HSP60, and HSP70 were also tested to evaluate autophagy. HIRI significantly increased ERS-dependent apoptosis markers and the number of apoptotic cells and damaged liver function. The ERS inhibitor salubrinal significantly alleviated liver injury in HIRI and OGD/R hepatocytes. Furthermore, both remote IPC and direct IPC significantly alleviated liver injury and inflammatory cell infiltration. IPC also upregulated LC3-II, downregulated p62 expression, and increased the mRNA levels of GRP78, HSP60, and HSP70 in HIRI mice and OGD/R hepatocytes, indicating the activation of autophagy by IPC. The autophagy inhibitor 3-methyladenine significantly attenuated the protective effects of IPC on ERS-dependent apoptosis and liver function, whereas the autophagy activator rapamycin mimicked the protective effects of IPC on ERS-dependent apoptosis in vivo and in vitro, suggesting a regulatory role of autophagy in ERS-dependent apoptosis. These results demonstrated that IPC could induce moderate autophagy and upregulate a few molecular chaperones to strengthen endogenous defense mechanisms, which is beneficial for alleviating ERS-dependent apoptosis and protecting hepatocytes from HIRI.
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Affiliation(s)
- Erliang Kong
- Department of Anesthesiology, The 988th Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Zhengzhou 450042, Henan, China; Department of Anesthesiology, Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Yongchang Li
- Department of Anesthesiology, Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Xuqiang Geng
- Department of Rheumatology and Immunology, Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Jianxin Wang
- Department of Anesthesiology, The 988th Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Zhengzhou 450042, Henan, China
| | - Yan He
- Department of Anesthesiology, Fuzhou Maternity and Child Health Care Hospital, Fuzhou 350000, Fujian, China.
| | - Xudong Feng
- Department of Anesthesiology, The 988th Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Zhengzhou 450042, Henan, China.
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Kusakabe J, Hata K, Tajima T, Miyauchi H, Zhao X, Kageyama S, Tsuruyama T, Hatano E. Properdin inhibition ameliorates hepatic ischemia/reperfusion injury without interfering with liver regeneration in mice. Front Immunol 2023; 14:1174243. [PMID: 37662914 PMCID: PMC10469474 DOI: 10.3389/fimmu.2023.1174243] [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: 02/26/2023] [Accepted: 07/28/2023] [Indexed: 09/05/2023] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (P <0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (P =0.010) and ssDNA+ cells (P <0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (P <0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (P =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines (P =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both P <0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (P =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.
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Affiliation(s)
- Jiro Kusakabe
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tetsuya Tajima
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidetaka Miyauchi
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Xiangdong Zhao
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tatsuaki Tsuruyama
- Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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11
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Tao S, Yu H, You T, Kong X, Wei X, Zheng Z, Zheng L, Feng Z, Huang B, Zhang X, Chen F, Chen X, Song H, Li J, Chen B, Chen J, Yao Q, Zhao F. A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche. ACS NANO 2023. [PMID: 37429012 DOI: 10.1021/acsnano.3c03828] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.
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Affiliation(s)
- Siyue Tao
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Hao Yu
- National Engineering Research Center of Ophthalmology and Optometry, School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang, China
| | - Tao You
- The First Affiliated Hospital of USTC, Division of Life Science and Medicine, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026 Anhui, China
| | - Xiangxi Kong
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Xiaoan Wei
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Zeyu Zheng
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Lin Zheng
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Zhenhua Feng
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Bao Huang
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Xuyang Zhang
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Feng Chen
- The First Affiliated Hospital of USTC, Division of Life Science and Medicine, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026 Anhui, China
| | - Xiao Chen
- The First Affiliated Hospital of USTC, Division of Life Science and Medicine, and CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026 Anhui, China
| | - Haixin Song
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
| | - Jie Li
- Department of Orthopaedic Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, 315100 Zhejiang, China
| | - Binhui Chen
- Department of Orthopaedic Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, 315100 Zhejiang, China
| | - Jian Chen
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
- Department of Orthopedic Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, 325000 Zhejiang, China
| | - Qingqing Yao
- National Engineering Research Center of Ophthalmology and Optometry, School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang, China
| | - Fengdong Zhao
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016 Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, 310016 Zhejiang, China
- Department of Orthopedic Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, 325000 Zhejiang, China
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12
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Lin C, Lei B, Dong C, Chen J, Chen S, Jiang K, Zeng Y, Su H, Jin H, Qiu X, Li Z, Hu Z, Yu S, Zhang C, Lu S, Atkinson C, Tomlinson S, Zhong F, Yuan G, He S. Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling. Am J Transplant 2023; 23:484-497. [PMID: 36746335 DOI: 10.1016/j.ajt.2023.01.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/21/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023]
Abstract
Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.
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Affiliation(s)
- Chengjie Lin
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Biao Lei
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Chunqiang Dong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Junze Chen
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Shilian Chen
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Keqing Jiang
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Yonglian Zeng
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Huizhao Su
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Hu Jin
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaoqiang Qiu
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Zeyuan Li
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Zhigao Hu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shuiping Yu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Cheng Zhang
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shiliu Lu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Fudi Zhong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China.
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China.
| | - Songqing He
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China; Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Nanning, Guangxi, China.
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13
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Li X, Su Q, Li W, Zhang X, Ran J. Analysis and identification of potential key genes in hepatic ischemia-reperfusion injury. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1375. [PMID: 36660667 PMCID: PMC9843403 DOI: 10.21037/atm-22-6171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/20/2022] [Indexed: 01/01/2023]
Abstract
Background Hepatic ischemia-reperfusion injury (HIRI) is an unavoidable surgical complication after liver transplantation, but current HIRI treatments cannot achieve satisfactory clinical outcomes. Thus, safer and more effective prevention and treatment methods need to be explored. Methods Transcriptome messenger ribonucleic acid (mRNA) and long non-coding RNA (lncRNA) sequencing data were obtained from male Sprague-Dawley rats, and these data were used to identify the differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE-lncRNAs) between the HIRI and control samples. A protein-protein interaction (PPI) network was also constructed for the DE-mRNAs to identify candidate genes, and the receiver operating characteristic curves of the 21 candidate genes were plotted to evaluate the diagnostic value of the candidate genes for HIRI. A random forest (RF) model, support vector machine model and generalized linear model were constructed based on the candidate genes. A gene set enrichment analysis (GSEA) of the key genes was conducted to determine the enriched pathways in the high expression groups. The miRWalk and miRanda database were used to constructed the lncRNA-miRNA-mRNA network. Finally, the expressions of the key genes were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Results A total of 256 DEGs and 67 DE-lncRNAs were identified in the HIRI and control samples. To explore the interactions between the DE-mRNAs, a PPI network of 130 DEGs was constructed. Further, 21 genes were selected as the candidate genes. Subsequently, 6 genes [i.e., Keratin-14 (Krt14), Uroplakin 3B (Upk3b), Keratin 7 (Krt7), Cadherin 3 (Cdh3), mesothelin (Msln), and Glypican 3 (Gpc3)] in the RF model were defined as the key genes. The GSEA results indicated that these key genes were enriched in the terms of extracellular structure organization, and extracellular matrix organization. Moreover, a lncRNA-miRNA-mRNA network was constructed with 4 lncRNAs, 5 mRNAs, and 11 miRNAs. Finally, the results indicated that the expression of Krt14, Upk3b, Msln, and Gpc3 were more highly expressed in the control samples than the HIRI samples. Conclusions A total of 6 key genes (i.e., Krt14, Upk3b, Krt7, Cdh3, Msln, and Gpc3) were identified. Our findings provide novel ideas for the diagnosis and treatment of HIRI.
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Affiliation(s)
- Xiaokai Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qiuming Su
- Department of Hepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Wang Li
- Department of Hepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Xibing Zhang
- Department of Hepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Jianghua Ran
- Department of Hepatopancreatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
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14
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Xu Z, Jiang N, Xiao Y, Yuan K, Wang Z. The role of gut microbiota in liver regeneration. Front Immunol 2022; 13:1003376. [PMID: 36389782 PMCID: PMC9647006 DOI: 10.3389/fimmu.2022.1003376] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/12/2022] [Indexed: 12/02/2022] Open
Abstract
The liver has unique regeneration potential, which ensures the continuous dependence of the human body on hepatic functions. As the composition and function of gut microbiota has been gradually elucidated, the vital role of gut microbiota in liver regeneration through gut-liver axis has recently been accepted. In the process of liver regeneration, gut microbiota composition is changed. Moreover, gut microbiota can contribute to the regulation of the liver immune microenvironment, thereby modulating the release of inflammatory factors including IL-6, TNF-α, HGF, IFN-γ and TGF-β, which involve in different phases of liver regeneration. And previous research have demonstrated that through enterohepatic circulation, bile acids (BAs), lipopolysaccharide, short-chain fatty acids and other metabolites of gut microbiota associate with liver and may promote liver regeneration through various pathways. In this perspective, by summarizing gut microbiota-derived signaling pathways that promote liver regeneration, we unveil the role of gut microbiota in liver regeneration and provide feasible strategies to promote liver regeneration by altering gut microbiota composition.
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Affiliation(s)
- Zhe Xu
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Nan Jiang
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Yuanyuan Xiao
- Department of Obstetrics and Gynecology, West China Second Hospital of Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
| | - Kefei Yuan
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
| | - Zhen Wang
- Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
- *Correspondence: Zhen Wang, ; Kefei Yuan, ; Yuanyuan Xiao,
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15
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Delaura IF, Gao Q, Anwar IJ, Abraham N, Kahan R, Hartwig MG, Barbas AS. Complement-targeting therapeutics for ischemia-reperfusion injury in transplantation and the potential for ex vivo delivery. Front Immunol 2022; 13:1000172. [PMID: 36341433 PMCID: PMC9626853 DOI: 10.3389/fimmu.2022.1000172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/05/2022] [Indexed: 01/21/2023] Open
Abstract
Organ shortages and an expanding waitlist have led to increased utilization of marginal organs. All donor organs are subject to varying degrees of IRI during the transplant process. Extended criteria organs, including those from older donors and organs donated after circulatory death are especially vulnerable to ischemia-reperfusion injury (IRI). Involvement of the complement cascade in mediating IRI has been studied extensively. Complement plays a vital role in the propagation of IRI and subsequent recruitment of the adaptive immune elements. Complement inhibition at various points of the pathway has been shown to mitigate IRI and minimize future immune-mediated injury in preclinical models. The recent introduction of ex vivo machine perfusion platforms provides an ideal window for therapeutic interventions. Here we review the role of complement in IRI by organ system and highlight potential therapeutic targets for intervention during ex vivo machine preservation of donor organs.
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Affiliation(s)
- Isabel F. Delaura
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Qimeng Gao
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Imran J. Anwar
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Nader Abraham
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Riley Kahan
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Matthew G. Hartwig
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, United States
| | - Andrew S. Barbas
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
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16
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Overexpression of miR-125a-5p Inhibits Hepatocyte Proliferation through the STAT3 Regulation In Vivo and In Vitro. Int J Mol Sci 2022; 23:ijms23158661. [PMID: 35955794 PMCID: PMC9369155 DOI: 10.3390/ijms23158661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 02/05/2023] Open
Abstract
microRNAs (miRNAs) are critically involved in liver regeneration (LR). miR-125a-5p (miR-125a) is a tumor-suppressing miRNA, but its role in LR has not been studied. Our previous studies have proved that miR-125a was related to LR at the initiation phase, while the mechanism hepatocyte proliferation triggered by miR-125a in LR has been rarely evaluated. Herein, we mainly studied the molecular mechanism of miR-125a in triggering hepatocyte proliferation and the proliferation stage of LR. Firstly, a striking reduction of miR-125a was found at 24 h as well as 30 h following partial hepatectomy (PH) in rat liver tissue by miRNAs expression profiles as well as qRT-PCR analysis. Furthermore, in vitro, upregulation of miR-125a decreased proliferation as well as G1/S conversion, which promoted hepatocytes apoptosis. STAT3 was the target of miR-125a. In vivo, upregulation of miR-125a by tail vein injection of agomir inhibited LR index. Upregulation of miR-125a inhibited LR index and hepatocytes proliferation by STAT3/p-STAT3/JUN/BCL2 axis. In summary, these current discoveries indicated that miR-125a inhibited hepatocytes proliferation as well as LR by targeting STAT3 and via acting on the STAT3/p-STAT3/JUN/BCL2 axis.
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Song W, Xiong X, Ge W, Zhu H. Prognostic value of protein biomarkers in liver transplantation: A systematic review. Proteomics Clin Appl 2022; 16:e2100038. [PMID: 35344271 DOI: 10.1002/prca.202100038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 01/30/2022] [Accepted: 03/22/2022] [Indexed: 12/30/2022]
Abstract
Liver transplantation is currently the preferred method for the treatment of advanced liver disease and early-stage hepatocellular carcinoma (HCC). Although advances in surgical techniques, immunosuppressive drugs and postoperative management have reduced the incidence of postoperative complications, how to effectively predict or diagnose postoperative complications earlier and reduce their incidence is still a clinical concern. We performed a comprehensive proteomics literature research to identified protein biomarkers in complications after liver transplantation. Seventeen studies met the inclusion criteria including ischemia reperfusion injury (IRI) (n = 4), acute rejection (AR) (n = 4), renal dysfunction (n = 4), HCC recurrence (n = 2), primary graft dysfunction (PGD) (n = 1), infection (n = 1), and liver fibrosis (n = 1). A total of 625 differentially expressed proteins (DEPs) have been reported between postoperative complications and controls, of which 63 have been validated by quantitative protein expression and 26 have been reported by at least two studies and showed consistently changes. The results of the bioinformation analysis show that the immune system, especially the innate immune system and cytokine signaling in immune system, is an important protein-mediated pathway that affects the prognosis of liver transplantation.
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Affiliation(s)
- Wei Song
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Xiaofu Xiong
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.,Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weihong Ge
- Department of Pharmacy, Nanjing Medical Center for Clinical Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Medical Center for Clinical Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China
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18
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Blasco M, Guillén-Olmos E, Diaz-Ricart M, Palomo M. Complement Mediated Endothelial Damage in Thrombotic Microangiopathies. Front Med (Lausanne) 2022; 9:811504. [PMID: 35547236 PMCID: PMC9082680 DOI: 10.3389/fmed.2022.811504] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 03/14/2022] [Indexed: 11/24/2022] Open
Abstract
Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management.
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Affiliation(s)
- Miquel Blasco
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain.,Institute of Biomedical Research August Pi i Sunyer (IDIPABS), Malalties Nefro-Urològiques i Trasplantament Renal, Barcelona, Spain
| | - Elena Guillén-Olmos
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), University of Barcelona, Barcelona, Spain
| | - Maribel Diaz-Ricart
- Hematopathology Unit, Department of Pathology, Hospital Clínic of Barcelona, Biomedical Diagnosis Centre (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Barcelona Endothelium Team, Barcelona, Spain
| | - Marta Palomo
- Hematopathology Unit, Department of Pathology, Hospital Clínic of Barcelona, Biomedical Diagnosis Centre (CDB), Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.,Barcelona Endothelium Team, Barcelona, Spain.,Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain
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19
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Abstract
Patients in the intensive care unit (ICU) often straddle the divide between life and death. Understanding the complex underlying pathomechanisms relevant to such situations may help intensivists select broadly acting treatment options that can improve the outcome for these patients. As one of the most important defense mechanisms of the innate immune system, the complement system plays a crucial role in a diverse spectrum of diseases that can necessitate ICU admission. Among others, myocardial infarction, acute lung injury/acute respiratory distress syndrome (ARDS), organ failure, and sepsis are characterized by an inadequate complement response, which can potentially be addressed via promising intervention options. Often, ICU monitoring and existing treatment options rely on massive intervention strategies to maintain the function of vital organs, and these approaches can further contribute to an unbalanced complement response. Artificial surfaces of extracorporeal organ support devices, transfusion of blood products, and the application of anticoagulants can all trigger or amplify undesired complement activation. It is, therefore, worth pursuing the evaluation of complement inhibition strategies in the setting of ICU treatment. Recently, clinical studies in COVID-19-related ARDS have shown promising effects of central inhibition at the level of C3 and paved the way for prospective investigation of this approach. In this review, we highlight the fundamental and often neglected role of complement in the ICU, with a special focus on targeted complement inhibition. We will also consider complement substitution therapies to temporarily counteract a disease/treatment-related complement consumption.
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20
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Howard MC, Nauser CL, Farrar CA, Sacks SH. Complement in ischaemia-reperfusion injury and transplantation. Semin Immunopathol 2021; 43:789-797. [PMID: 34757496 PMCID: PMC8579729 DOI: 10.1007/s00281-021-00896-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/22/2021] [Indexed: 01/08/2023]
Abstract
Until recently, the only known condition in which complement could mediate transplant injury was the rare occurrence of antibody-mediated rejection, in which the original concept of antibody immunity against the transplant was supported by complementary proteins present in the serum. This has changed within the last two decades because of evidence that the processes of ischaemia–reperfusion injury followed by T cell–mediated rejection are also critically dependent on components generated by the complement system. We now have a clearer understanding of the complement triggers and effectors that mediate injury, and a detailed map of their local sites of production and activation in the kidney. This is providing helpful guidelines as to how these harmful processes that restrict transplant outcomes can be targeted for therapeutic benefit. Here we review some of the recent advances highlighting relevant therapeutic targets.
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Affiliation(s)
- Mark C Howard
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
| | - Christopher L Nauser
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Conrad A Farrar
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Steven H Sacks
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
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21
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Cockram TOJ, Dundee JM, Popescu AS, Brown GC. The Phagocytic Code Regulating Phagocytosis of Mammalian Cells. Front Immunol 2021; 12:629979. [PMID: 34177884 PMCID: PMC8220072 DOI: 10.3389/fimmu.2021.629979] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 05/18/2021] [Indexed: 01/21/2023] Open
Abstract
Mammalian phagocytes can phagocytose (i.e. eat) other mammalian cells in the body if they display certain signals, and this phagocytosis plays fundamental roles in development, cell turnover, tissue homeostasis and disease prevention. To phagocytose the correct cells, phagocytes must discriminate which cells to eat using a 'phagocytic code' - a set of over 50 known phagocytic signals determining whether a cell is eaten or not - comprising find-me signals, eat-me signals, don't-eat-me signals and opsonins. Most opsonins require binding to eat-me signals - for example, the opsonins galectin-3, calreticulin and C1q bind asialoglycan eat-me signals on target cells - to induce phagocytosis. Some proteins act as 'self-opsonins', while others are 'negative opsonins' or 'phagocyte suppressants', inhibiting phagocytosis. We review known phagocytic signals here, both established and novel, and how they integrate to regulate phagocytosis of several mammalian targets - including excess cells in development, senescent and aged cells, infected cells, cancer cells, dead or dying cells, cell debris and neuronal synapses. Understanding the phagocytic code, and how it goes wrong, may enable novel therapies for multiple pathologies with too much or too little phagocytosis, such as: infectious disease, cancer, neurodegeneration, psychiatric disease, cardiovascular disease, ageing and auto-immune disease.
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Affiliation(s)
| | | | | | - Guy C. Brown
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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22
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Riddiough GE, Jalal Q, Perini MV, Majeed AW. Liver regeneration and liver metastasis. Semin Cancer Biol 2021; 71:86-97. [PMID: 32532594 DOI: 10.1016/j.semcancer.2020.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
Surgical resection for primary and secondary hepatic neoplasms provides the best chance of cure. Advanced surgical techniques such as portal vein embolisation, two-staged hepatectomy and associated liver partition and portal vein ligation for staged-hepatectomy (ALPPS) have facilitated hepatic resection in patients with previously unresectable, bi-lobar disease. These techniques are frequently employed to ensure favourable clinical outcomes and avoid potentially fatal post-operative complications such as small for size syndrome and post-hepatectomy liver failure. However, they rely on the innate ability of the liver to regenerate. As our knowledge of liver organogenesis, liver regeneration and hepatocarcinogenesis has expanded in recent decades it has come to light that liver regeneration may also drive tumour recurrence. Clinical studies in patients undergoing portal vein embolisation indicate that tumours may progress following the procedure in concordance with liver regeneration and hypertrophy, however overall survival in these patients has not been shown to be worse. In this article, we delve into the mechanisms underlying liver regeneration to better understand the complex ways in which this may affect tumour behaviour and ultimately inform clinical decisions.
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Affiliation(s)
- Georgina E Riddiough
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Qaiser Jalal
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
| | - Marcos V Perini
- Department of Surgery at Austin Health, The University of Melbourne, Level 8, Lance Townsend Building, 145 Studley Road, Heidelberg, VIC 3084, Australia.
| | - Ali W Majeed
- Sheffield Teaching Hospitals, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.
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23
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Hu ZG, Zhou Y, Lin CJ, Yuan GD, He SQ. Emerging recognition of the complement system in hepatic ischemia/reperfusion injury, liver regeneration and recovery (Review). Exp Ther Med 2021; 21:223. [PMID: 33603832 PMCID: PMC7851628 DOI: 10.3892/etm.2021.9654] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 11/26/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is a result of the ischemic cascade and may occur in the settings of liver trauma, resection and transplantation. Components of the complement system have been indicated to be mediators of hepatic IRI and regulators of liver regeneration. As such, their potential to mediate both beneficial and harmful effects render them key targets for therapy. In the present study, the mechanisms of complement mediating hepatic IRI were discussed with a focus on the different functions of complement in hepatic injury and liver recovery, and an explanation for this apparent paradox is provided, i.e. that the complement products C3a and C5a have an important role in liver damage; however, C3a and C5a are also necessary for liver regeneration. Furthermore, situated at the end of the complement activation cascade, the membrane attack complex is crucial in hepatic IRI and inhibiting the complex with a site-targeted murine complement inhibitor, complement receptor 2-CD59, may improve liver regeneration after partial hepatectomy, even when hepatectomy is combined with ischemia and reperfusion.
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Affiliation(s)
- Zhi-Gao Hu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Zhou
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Cheng-Jie Lin
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Guan-Dou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Song-Qing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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24
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Gao M, Dong Q, Wang W, Yang Z, Guo L, Lu Y, Ding B, Chen L, Zhang J, Xu R. Induced neural stem cell grafts exert neuroprotection through an interaction between Crry and Akt in a mouse model of closed head injury. Stem Cell Res Ther 2021; 12:128. [PMID: 33579360 PMCID: PMC7881465 DOI: 10.1186/s13287-021-02186-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/24/2021] [Indexed: 12/26/2022] Open
Abstract
Background Recently, growing evidence has indicated an important role of the complement system, a crucial component of immunity, in mediating neuroinflammation and promoting neuronal apoptosis following closed head injury (CHI). We previously reported that transplanted induced neural stem cells (iNSCs) pre-treated with CHI mouse serum could enhance complement receptor type 1-related protein y (Crry) expression and ameliorate complement-mediated damage in mouse CHI models. However, the mechanism underlying the elevated levels of Crry expression remains elusive. Methods CHI models were established using a standardized weight-drop device. We collected CHI mouse serum at 12 h post-trauma. RT-QPCR assay, western blot analysis, complement deposition assay, Akt inhibition assay, flow cytometry, cell transplantation, and functional assay were utilized to clarify the mechanism of Crry expression in iNSCs receiving CHI mouse serum treatment. Results We observed dramatic increases in the levels of Crry expression and Akt activation in iNSCs receiving CHI mouse serum treatment. Remarkably, Akt inhibition led to the reduction of Crry expression in iNSCs. Intriguingly, the treatment of iNSC-derived neurons with recombinant complement receptor 2-conjugated Crry (CR2-Crry), which inhibits all complement pathways, substantially enhanced Crry expression and Akt activation in neurons after CHI mouse serum treatment. In subsequent in vitro experiments of pre-treatment of iNSCs with CR2-Crry, we observed significant increases in the levels of Crry expression and Akt activation in iNSCs and iNSC-derived astrocytes and neurons post-treatment with CHI mouse serum. Additionally, an in vivo study showed that intracerebral-transplanted iNSCs pre-treated with CR2-Crry markedly enhanced Crry expression in neurons and protected neurons from complement-dependent damage in the brains of CHI mice. Conclusion INSCs receiving CR2-Crry pre-treatment increased the levels of Crry expression in iNSCs and iNSC-derived astrocytes and neurons and attenuated complement-mediated injury following CHI. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02186-z.
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Affiliation(s)
- Mou Gao
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.,Department of Neurosurgery, The PLA General Hospital, Beijing, 100853, China
| | - Qin Dong
- Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing, 100038, China
| | - Wenjia Wang
- Department of ENT-HN, Hainan Hospital of PLA General Hospital, Sanya, 572013, China
| | - Zhijun Yang
- Department of Neurosurgery, The Seventh Medical Center, The PLA General Hospital, Beijing, 100700, China
| | - Lili Guo
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yingzhou Lu
- Department of Obstetrics, Fu Xing Hospital, Capital Medical University, Beijing, 100038, China
| | - Boyun Ding
- Department of Neurosurgery, The Seventh Medical Center, The PLA General Hospital, Beijing, 100700, China
| | - Lihua Chen
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Jianning Zhang
- Department of Neurosurgery, The PLA General Hospital, Beijing, 100853, China.
| | - Ruxiang Xu
- Department of Neurosurgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China. .,Department of Neurosurgery, The Seventh Medical Center, The PLA General Hospital, Beijing, 100700, China.
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25
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Vandendriessche S, Cambier S, Proost P, Marques PE. Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front Cell Dev Biol 2021; 9:624025. [PMID: 33644062 PMCID: PMC7905230 DOI: 10.3389/fcell.2021.624025] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.
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Affiliation(s)
- Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Seppe Cambier
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
| | - Pedro E Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
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26
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Complement 5 Inhibition Ameliorates Hepatic Ischemia/reperfusion Injury in Mice, Dominantly via the C5a-mediated Cascade. Transplantation 2021; 104:2065-2077. [PMID: 32384381 DOI: 10.1097/tp.0000000000003302] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatic ischemia/reperfusion injury (IRI) is a serious complication in liver surgeries, including transplantation. Complement activation seems to be closely involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Complement 5 (C5)-targeted regulation in hepatic IRI. METHODS C5-knockout (B10D2/oSn) and their corresponding wild-type mice (WT, B10D2/nSn) were exposed to 90-minute partial (70%) hepatic ischemia/reperfusion with either anti-mouse-C5 monoclonal antibody (BB5.1) or corresponding control immunoglobulin administration 30 minutes before ischemia. C5a receptor 1 antagonist was also given to WT to identify which cascade, C5a or C5b-9, is dominant. RESULTS C5-knockout and anti-C5-Ab administration to WT both significantly reduced serum transaminase release and histopathological damages from 2 hours after reperfusion. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and decreased high-mobility group box 1 release. After 6 hours of reperfusion, the infiltration of CD11+ and Ly6-G+ cells, cytokine/chemokine expression, single-stranded DNA+ cells, and cleaved caspase-3 expression were all significantly alleviated by anti-C5-Ab. C5a receptor 1 antagonist was as effective as anti-C5-Ab for reducing transaminases. CONCLUSIONS Anti-C5 antibody significantly ameliorated hepatic IRI, predominantly via the C5a-mediated cascade, not only by inhibiting platelet aggregation during the early phase but also by attenuating the activation of infiltrating macrophages/neutrophils and hepatocyte apoptosis in the late phase of reperfusion. Given its efficacy, clinical availability, and controllability, C5-targeted intervention may provide a novel therapeutic strategy against hepatic IRI.
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Abstract
ABSTRACT As an integral component of cardiac tissue, macrophages are critical for cardiac development, adult heart homeostasis, as well as cardiac healing. One fundamental function of macrophages involves the clearance of dying cells or debris, a process termed efferocytosis. Current literature primarily pays attention to the impact of efferocytosis on apoptotic cells. However, emerging evidence suggests that necrotic cells and their released cellular debris can also be removed by cardiac macrophages through efferocytosis. Importantly, recent studies have demonstrated that macrophage efferocytosis plays an essential role in cardiac pathophysiology and repair. Therefore, understanding macrophage efferocytosis would provide valuable insights on cardiac health, and may offer new therapeutic strategies for the treatment of patients with heart failure. In this review, we first summarize the molecular signals that are associated with macrophage efferocytosis of apoptotic and necrotic cells, and then discuss how the linkage of efferocytosis to the resolution of inflammation affects cardiac function and recovery under normal and diseased conditions. Lastly, we highlight new discoveries related to the effects of macrophage efferocytosis on cardiac injury and repair.
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Affiliation(s)
- Li Yutian
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Li Qianqian
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Pharmaceutical Science, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio
| | - Guo-Chang Fan
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio
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28
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Dihydro-stilbene gigantol relieves CCl 4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver. Acta Pharmacol Sin 2020; 41:1433-1445. [PMID: 32404983 DOI: 10.1038/s41401-020-0406-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 03/23/2020] [Indexed: 12/22/2022]
Abstract
In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg-1· d-1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.
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29
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Huber-Lang MS, Ignatius A, Köhl J, Mannes M, Braun CK. Complement in trauma-Traumatised complement? Br J Pharmacol 2020; 178:2863-2879. [PMID: 32880897 DOI: 10.1111/bph.15245] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/23/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022] Open
Abstract
Physical trauma represents a major global burden. The trauma-induced response, including activation of the innate immune system, strives for regeneration but can also lead to post-traumatic complications. The complement cascade is rapidly activated by damaged tissue, hypoxia, exogenous proteases and others. Activated complement can sense, mark and clear both damaged tissue and pathogens. However, excessive and insufficient activation of complement can result in a dysfunctional immune and organ response. Similar to acute coagulopathy, complementopathy can develop with enhanced anaphylatoxin generation and an impairment of complement effector functions. Various remote organ effects are induced or modulated by complement activation. Frequently, established trauma treatments are double-edged. On one hand, they help stabilising haemodynamics and oxygen supply as well as injured organs and on the other hand, they also drive complement activation. Immunomodulatory approaches aim to reset trauma-induced disbalance of complement activation and thus may change surgical trauma management procedures to improve outcome. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Markus S Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Anita Ignatius
- Institue of Orthopaedic Research and Biomechanics, University Hospital of Ulm, Ulm, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammatory Research, University of Lübeck, Lübeck, Germany.,Division of Immunobiology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Marco Mannes
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany
| | - Christian Karl Braun
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany.,Department of Paediatrics and Adolescent Medicine, University Hospital of Ulm, Ulm, Germany
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Xie CB, Jane-Wit D, Pober JS. Complement Membrane Attack Complex: New Roles, Mechanisms of Action, and Therapeutic Targets. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1138-1150. [PMID: 32194049 DOI: 10.1016/j.ajpath.2020.02.006] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/24/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
Abstract
The complement membrane attack complex (MAC) is classically known as a cytolytic effector of innate and adaptive immunity that forms pores in the plasma membrane of pathogens or targeted cells, leading to osmolysis. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. In the absence of lysis, MAC may induce intracellular signaling and cell activation, responses implicated in a variety of autoimmune, inflammatory, and transplant disease settings. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. MAC-activated cells have been found to express proinflammatory proteins-often through NF-κB-dependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1β and IL-18, as well as other signaling pathways. These recent insights into the mechanisms of action of MAC provide an updated framework to therapeutic approaches that can target MAC assembly, signaling, and proinflammatory effects in various complement-mediated diseases.
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Affiliation(s)
- Catherine B Xie
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut
| | - Dan Jane-Wit
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Jordan S Pober
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
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31
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Morigi M, Perico L, Corna D, Locatelli M, Cassis P, Carminati CE, Bolognini S, Zoja C, Remuzzi G, Benigni A, Buelli S. C3a receptor blockade protects podocytes from injury in diabetic nephropathy. JCI Insight 2020; 5:131849. [PMID: 32161193 DOI: 10.1172/jci.insight.131849] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 01/29/2020] [Indexed: 12/14/2022] Open
Abstract
Renal activation of the complement system has been described in patients with diabetic nephropathy (DN), although its pathological relevance is still ill-defined. Here, we studied whether glomerular C3a, generated by uncontrolled complement activation, promotes podocyte damage, leading to proteinuria and renal injury in mice with type 2 diabetes. BTBR ob/ob mice exhibited podocyte loss, albuminuria, and glomerular injury accompanied by C3 deposits and increased C3a and C3a receptor (C3aR) levels. Decreased glomerular nephrin and α-actinin4 expression, coupled with integrin-linked kinase induction, were also observed. Treatment of DN mice with a C3aR antagonist enhanced podocyte density and preserved their phenotype, limiting proteinuria and glomerular injury. Mechanistically, ultrastructural and functional mitochondrial alterations, accompanied by downregulation of antioxidant superoxide dismutase 2 (SOD2) and increased protein oxidation, occurred in podocytes and were normalized by C3aR blockade. In cultured podocytes, C3a induced cAMP-dependent mitochondrial fragmentation. Alterations of mitochondrial membrane potential, SOD2 expression, and energetic metabolism were also found in response to C3a. Notably, C3a-induced podocyte motility was inhibited by SS-31, a peptide with mitochondrial protective effects. These data indicate that C3a blockade represents a potentially novel therapeutic strategy in DN for preserving podocyte integrity through the maintenance of mitochondrial functions.
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Affiliation(s)
- Marina Morigi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Luca Perico
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Daniela Corna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Monica Locatelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Paola Cassis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Claudia Elisa Carminati
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Silvia Bolognini
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Carlamaria Zoja
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.,"L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Simona Buelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
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32
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Greenbaum LE, Ukomadu C, Tchorz JS. Clinical translation of liver regeneration therapies: A conceptual road map. Biochem Pharmacol 2020; 175:113847. [PMID: 32035080 DOI: 10.1016/j.bcp.2020.113847] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/04/2020] [Indexed: 02/07/2023]
Abstract
The increasing incidence of severe liver diseases worldwide has resulted in a high demand for curative liver transplantation. Unfortunately, the need for transplants by far eclipses the availability of suitable grafts leaving many waitlisted patients to face liver failure and often death. Routine use of smaller grafts (for example left lobes, split livers) from living or deceased donors could increase the number of life-saving transplants but is often limited by the graft versus recipient weight ratio defining the safety margins that minimize the risk of small for size syndrome (SFSS). SFSS is a severe complication characterized by failure of a small liver graft to regenerate and occurs when a donor graft is insufficient to meet the metabolic demand of the recipient, leading to liver failure as a result of insufficient liver mass. SFSS is not limited to transplantation but can also occur in the setting of hepatic surgical resections, where life-saving large resections of tumors may be limited by concerns of post-surgical liver failure. There are, as yet no available pro-regenerative therapies to enable liver regrowth and thus prevent SFSS. However, there is optimism around targeting factors and pathways that have been identified as regulators of liver regeneration to induce regrowth in vivo and ex vivo for clinical use. In this commentary, we propose a roadmap for developing such pro-regenerative therapy and for bringing it into the clinic. We summarize the clinical indications, preclinical models, pro-regenerative pathways and safety considerations necessary for developing such a drug.
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Affiliation(s)
- Linda E Greenbaum
- Novartis Institutes for Biomedical Research, Novartis Pharma AG, East Hanover, NJ, United States.
| | - Chinweike Ukomadu
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA, United States.
| | - Jan S Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
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33
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Werneburg S, Jung J, Kunjamma RB, Ha SK, Luciano NJ, Willis CM, Gao G, Biscola NP, Havton LA, Crocker SJ, Popko B, Reich DS, Schafer DP. Targeted Complement Inhibition at Synapses Prevents Microglial Synaptic Engulfment and Synapse Loss in Demyelinating Disease. Immunity 2020; 52:167-182.e7. [PMID: 31883839 PMCID: PMC6996144 DOI: 10.1016/j.immuni.2019.12.004] [Citation(s) in RCA: 265] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 10/30/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases. VIDEO ABSTRACT.
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Affiliation(s)
- Sebastian Werneburg
- Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Jonathan Jung
- Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Rejani B Kunjamma
- Department of Neurology, University of Chicago, Chicago, IL 60637, USA
| | - Seung-Kwon Ha
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicholas J Luciano
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cory M Willis
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06032, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiologic and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Natalia P Biscola
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Leif A Havton
- Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Stephen J Crocker
- Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06032, USA
| | - Brian Popko
- Department of Neurology, University of Chicago, Chicago, IL 60637, USA
| | - Daniel S Reich
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dorothy P Schafer
- Department of Neurobiology, Brudnik Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Westman J, Grinstein S, Marques PE. Phagocytosis of Necrotic Debris at Sites of Injury and Inflammation. Front Immunol 2020; 10:3030. [PMID: 31998312 PMCID: PMC6962235 DOI: 10.3389/fimmu.2019.03030] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
Clearance of cellular debris is required to maintain the homeostasis of multicellular organisms. It is intrinsic to processes such as tissue growth and remodeling, regeneration and resolution of injury and inflammation. Most of the removal of effete and damaged cells is performed by macrophages and neutrophils through phagocytosis, a complex phenomenon involving ingestion and degradation of the disposable particles. The study of the clearance of cellular debris has been strongly biased toward the removal of apoptotic bodies; as a result, the mechanisms underlying the removal of necrotic cells have remained relatively unexplored. Here, we will review the incipient but growing knowledge of the phagocytosis of necrotic debris, from their recognition and engagement to their internalization and disposal. Critical insights into these events were gained recently through the development of new in vitro and in vivo models, along with advances in live-cell and intravital microscopy. This review addresses the classes of "find-me" and "eat-me" signals presented by necrotic cells and their cognate receptors in phagocytes, which in most cases differ from the extensively characterized counterparts in apoptotic cell engulfment. The roles of damage-associated molecular patterns, chemokines, lipid mediators, and complement components in recruiting and activating phagocytes are reviewed. Lastly, the physiological importance of necrotic cell removal is emphasized, highlighting the key role of impaired debris clearance in autoimmunity.
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Affiliation(s)
- Johannes Westman
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Sergio Grinstein
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, Canada.,Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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35
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Gong Y, Liu H, Tao L. Cajanonic acid A regulates the ratio of Th17/Treg via inhibition of expression of IL-6 and TGF-β in insulin-resistant HepG2 cells. Biosci Rep 2019; 39:BSR20181716. [PMID: 31729529 PMCID: PMC6928521 DOI: 10.1042/bsr20181716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 07/01/2019] [Accepted: 09/18/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The objectives of the present study are to investigate whether cajanonic acid A (CAA) can reduce insulin resistance (IR) in HepG2 cells and to gain a preliminary understanding of the mechanisms underlying this effect. METHODS Following induction of IR in HepG2 cells, we tested the regulatory effect of CAA on glucose consumption and evaluated hepatocyte production of IL-6, TGF-β, and key molecules in the insulin transduction pathway. A transwell co-culturing system was used to assess the effect of CAA on IR in HepG2 cells during the differentiation of CD4+ T cells by calculating the ratio of (Th17)/regulatory T cell (Treg). We evaluated the effect of CAA on the expression of IL-17RC cells and HepG2 cell apoptosis by immunofluorescence and flow cytometry assay. RESULTS CAA improved dexamethasone-induced reduction in glucose consumption in HepG2 cells, inhibited hepatocyte production of IL-6 and TGF-β, increased the expression of IL-17RC cell, and increased cellular apoptosis in insulin-resistant HepG2 cells. When co-cultured with CD4+ T cells, insulin-resistant HepG2 cells induced a decrease in the ratio of Th17/Treg, but CAA dampened the effect. Application of IL-6 and TGF-β, together with CAA, reversed the effect of CAA on insulin-resistant HepG2 cells. Overexpression of IL17R, however, counteracted the effect of IL-6 neutralizing antibody within the culture system. CONCLUSION CAA can regulate the ratio of Th17/Treg by mediating the expression of IL-6 and TGF-β in insulin-resistant HepG2 cells.
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Affiliation(s)
- Yanfeng Gong
- Department of Geriatrics, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Zheng Street, Nanchang 330006, Jiangxi, China
| | - Huanbing Liu
- Department of Geriatrics, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Zheng Street, Nanchang 330006, Jiangxi, China
| | - Liming Tao
- Department of Geriatrics, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Zheng Street, Nanchang 330006, Jiangxi, China
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36
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Thorgersen EB, Barratt‐Due A, Haugaa H, Harboe M, Pischke SE, Nilsson PH, Mollnes TE. The Role of Complement in Liver Injury, Regeneration, and Transplantation. Hepatology 2019; 70:725-736. [PMID: 30653682 PMCID: PMC6771474 DOI: 10.1002/hep.30508] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 01/10/2019] [Indexed: 12/20/2022]
Abstract
The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.
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Affiliation(s)
- Ebbe Billmann Thorgersen
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Department of Gastroenterological SurgeryThe Norwegian Radium Hospital, Oslo University HospitalOsloNorway
| | - Andreas Barratt‐Due
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway
| | - Håkon Haugaa
- Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway,Lovisenberg Diaconal University CollegeOsloNorway
| | - Morten Harboe
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway
| | - Søren Erik Pischke
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Division of Emergencies and Critical CareOslo University Hospital RikshospitaletOsloNorway
| | - Per H. Nilsson
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Linnaeus Centre for Biomaterials ChemistryLinnaeus UniversityKalmarSweden
| | - Tom Eirik Mollnes
- Department of ImmunologyOslo University Hospital Rikshospitalet and University of OsloOsloNorway,Reserach Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TRECUniversity of TromsøTromsøNorway,Centre of Molecular Inflammation ResearchNorwegian University of Science and TechnologyTrondheimNorway
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37
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Zhong F, Hu Z, Jiang K, Lei B, Wu Z, Yuan G, Luo H, Dong C, Tang B, Zheng C, Yang S, Zeng Y, Guo Z, Yu S, Su H, Zhang G, Qiu X, Tomlinson S, He S. Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis. Cell Res 2019; 29:548-561. [PMID: 31076642 PMCID: PMC6796853 DOI: 10.1038/s41422-019-0175-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 04/12/2019] [Indexed: 12/23/2022] Open
Abstract
Complement is known to play a role in alcoholic fatty liver disease (AFLD), but the underlying mechanisms are poorly understood, thereby constraining the development of a rational approach for therapeutic intervention in the complement system. C3 deficiency has been shown to impart protective effects against ethanol-induced hepatic steatosis and inflammation. Here we demonstrate a protection effect in wild-type mice by treatment with CR2-Crry, a specific inhibitor of C3 activation. The expression of glycine transfer (t) RNA-derived fragments (Gly-tRFs) is upregulated in ethanol-fed mice and inhibition of Gly-tRFs in vivo decreases chronic ethanol feeding-induced hepatosteatosis without affecting inflammation. The expression of Gly-tRF was downregulated in C3-deficient or CR2-Crry-treated mice, but not in C5-deficient mice; Gly-tRF expression was restored by the C3 activation products C3a or Asp (C3a-des-Arg) via the regulation of CYP2E1. Transcriptome profiling of hepatic tissues showed that Gly-tRF inhibitors upregulate the expression of sirtuin1 (Sirt1) and subsequently affect downstream lipogenesis and β-oxidation pathways. Mechanistically, Gly-tRF interacts with AGO3 to downregulate Sirt1 expression via sequence complementarity in the 3' UTR. Notably, the expression levels of C3d, CYP2E1 and Gly-tRF are upregulated, whereas Sirt1 is decreased in AFLD patients compared to healthy controls. Collectively, our findings suggest that C3 activation products contribute to hepatosteatosis by regulating the expression of Gly-tRF. Complement inhibition at the C3 activation step and treatment with Gly-tRF inhibitors may be potential and precise therapeutic approaches for AFLD.
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Affiliation(s)
- Fudi Zhong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhigao Hu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
- Laboratory of Liver Injury and Repair, Nanning, Guangxi, China
| | - Keqing Jiang
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Biao Lei
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhan Wu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Hongliang Luo
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chunqiang Dong
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Bo Tang
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chaowen Zheng
- Laboratory of Liver Injury and Repair, Nanning, Guangxi, China
| | - Shuai Yang
- Laboratory of Liver Injury and Repair, Nanning, Guangxi, China
| | - Yonglian Zeng
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhenya Guo
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Shuiping Yu
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Huizhao Su
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Guo Zhang
- Department of Gastroenterology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Xiaoqiang Qiu
- Laboratory of Liver Injury and Repair, Nanning, Guangxi, China
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Songqing He
- Division of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
- Laboratory of Liver Injury and Repair, Nanning, Guangxi, China.
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Zhou H, Hara H, Cooper DK. The complex functioning of the complement system in xenotransplantation. Xenotransplantation 2019; 26:e12517. [PMID: 31033064 PMCID: PMC6717021 DOI: 10.1111/xen.12517] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 03/15/2019] [Accepted: 03/22/2019] [Indexed: 12/25/2022]
Abstract
The role of complement in xenotransplantation is well-known and is a topic that has been reviewed previously. However, our understanding of the immense complexity of its interaction with other constituents of the innate immune response and of the coagulation, adaptive immune, and inflammatory responses to a xenograft is steadily increasing. In addition, the complement system plays a function in metabolism and homeostasis. New reviews at intervals are therefore clearly warranted. The pathways of complement activation, the function of the complement system, and the interaction between complement and coagulation, inflammation, and the adaptive immune system in relation to xenotransplantation are reviewed. Through several different mechanisms, complement activation is a major factor in contributing to xenograft failure. In the organ-source pig, the detrimental influence of the complement system is seen during organ harvest and preservation, for example, in ischemia-reperfusion injury. In the recipient, the effect of complement can be seen through its interaction with the immune, coagulation, and inflammatory responses. Genetic-engineering and other therapeutic methods by which the xenograft can be protected from the effects of complement activation are discussed. The review provides an updated source of reference to this increasingly complex subject.
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Affiliation(s)
- Hongmin Zhou
- Department of Cardiothoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David K.C. Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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Ma Y, Liu Y, Zhang Z, Yang GY. Significance of Complement System in Ischemic Stroke: A Comprehensive Review. Aging Dis 2019; 10:429-462. [PMID: 31011487 PMCID: PMC6457046 DOI: 10.14336/ad.2019.0119] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/19/2019] [Indexed: 12/14/2022] Open
Abstract
The complement system is an essential part of innate immunity, typically conferring protection via eliminating pathogens and accumulating debris. However, the defensive function of the complement system can exacerbate immune, inflammatory, and degenerative responses in various pathological conditions. Cumulative evidence indicates that the complement system plays a critical role in the pathogenesis of ischemic brain injury, as the depletion of certain complement components or the inhibition of complement activation could reduce ischemic brain injury. Although multiple candidates modulating or inhibiting complement activation show massive potential for the treatment of ischemic stroke, the clinical availability of complement inhibitors remains limited. The complement system is also involved in neural plasticity and neurogenesis during cerebral ischemia. Thus, unexpected side effects could be induced if the systemic complement system is inhibited. In this review, we highlighted the recent concepts and discoveries of the roles of different kinds of complement components, such as C3a, C5a, and their receptors, in both normal brain physiology and the pathophysiology of brain ischemia. In addition, we comprehensively reviewed the current development of complement-targeted therapy for ischemic stroke and discussed the challenges of bringing these therapies into the clinic. The design of future experiments was also discussed to better characterize the role of complement in both tissue injury and recovery after cerebral ischemia. More studies are needed to elucidate the molecular and cellular mechanisms of how complement components exert their functions in different stages of ischemic stroke to optimize the intervention of targeting the complement system.
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Affiliation(s)
- Yuanyuan Ma
- 1Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,2Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yanqun Liu
- 3Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhijun Zhang
- 2Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Yuan Yang
- 1Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,2Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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van Zanden JE, Jager NM, Daha MR, Erasmus ME, Leuvenink HGD, Seelen MA. Complement Therapeutics in the Multi-Organ Donor: Do or Don't? Front Immunol 2019; 10:329. [PMID: 30873176 PMCID: PMC6400964 DOI: 10.3389/fimmu.2019.00329] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
Over the last decade, striking progress has been made in the field of organ transplantation, such as better surgical expertise and preservation techniques. Therefore, organ transplantation is nowadays considered a successful treatment in end-stage diseases of various organs, e.g. the kidney, liver, intestine, heart, and lungs. However, there are still barriers which prevent a lifelong survival of the donor graft in the recipient. Activation of the immune system is an important limiting factor in the transplantation process. As part of this pro-inflammatory environment, the complement system is triggered. Complement activation plays a key role in the transplantation process, as highlighted by the amount of studies in ischemia-reperfusion injury (IRI) and rejection. However, new insight have shown that complement is not only activated in the later stages of transplantation, but already commences in the donor. In deceased donors, complement activation is associated with deteriorated quality of deceased donor organs. Of importance, since most donor organs are derived from either brain-dead donors or deceased after circulatory death donors. The exact mechanisms and the role of the complement system in the pathophysiology of the deceased donor have been underexposed. This review provides an overview of the current knowledge on complement activation in the (multi-)organ donor. Targeting the complement system might be a promising therapeutic strategy to improve the quality of various donor organs. Therefore, we will discuss the complement therapeutics that already have been tested in the donor. Finally, we question whether complement therapeutics should be translated to the clinics and if all organs share the same potential complement targets, considering the physiological differences of each organ.
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Affiliation(s)
- Judith E. van Zanden
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Neeltina M. Jager
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Mohamed R. Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
| | - Michiel E. Erasmus
- Department of Thoracic Surgery, University Medical Center Groningen, Groningen, Netherlands
| | | | - Marc A. Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
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Boteon YL, Boteon APCS, Attard J, Mergental H, Mirza DF, Bhogal RH, Afford SC. Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review. Am J Transplant 2018; 18:2384-2399. [PMID: 29947472 DOI: 10.1111/ajt.14992] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/13/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies.
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Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Amanda P C S Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joseph Attard
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ricky H Bhogal
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon C Afford
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
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Tissue-targeted complement therapeutics. Mol Immunol 2018; 102:120-128. [PMID: 30220307 DOI: 10.1016/j.molimm.2018.06.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/04/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023]
Abstract
Complement activation contributes to the pathogenesis of numerous inflammatory and autoimmune diseases. Therapeutic complement inhibitors have proven effective in several of these diseases and have now entered clinical use. Complement activation has multiple different biologic effects, however, and the currently available drugs can have undesirable side-effects, such as an increased risk of infection. Several different complement inhibitors have been developed that bind to target molecules, thereby concentrating the drug at a specific anatomic site. This approach appears to be both more effective than untargeted drugs and to have fewer side effects. In this article we review different targeting strategies that have been developed and the evidence supporting the use and benefits of targeted drugs.
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Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury. J Neurosci 2018; 38:2519-2532. [PMID: 29437855 DOI: 10.1523/jneurosci.2197-17.2018] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 01/03/2018] [Accepted: 01/29/2018] [Indexed: 12/28/2022] Open
Abstract
The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that although inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.SIGNIFICANCE STATEMENT Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.
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Neutrophils: a cornerstone of liver ischemia and reperfusion injury. J Transl Med 2018; 98:51-62. [PMID: 28920945 DOI: 10.1038/labinvest.2017.90] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 07/05/2017] [Accepted: 07/09/2017] [Indexed: 12/12/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is the main cause of morbidity and mortality due to graft rejection after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. This hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion phase, and is characterized by a large neutrophil recruitment to the liver. Production of cytokines, chemokines, and danger signals results in activation of resident hepatocytes, leukocytes, and Kupffer cells. The role of neutrophils as the main amplifiers of liver injury in IRI has been recognized in many publications. Several studies have shown that elimination of excessive neutrophils or inhibition of their function leads to reduction of liver injury and inflammation. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. In addition, the molecules necessary for this type of migration are poorly defined, as the liver presents an atypical sinusoidal vasculature in which the classical leukocyte migration paradigm only partially applies. This review summarizes recent advances in neutrophil-mediated liver damage, and its application to liver IRI. Basic mechanisms of activation of neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of danger signals, adhesion molecules, chemokines, glycosaminoglycans (GAGs), and metalloproteinases is explored. The precise definition of the molecular events that govern the recruitment of neutrophils and their movement into inflamed tissue may offer new therapeutic alternatives for hepatic injury by IRI and other inflammatory diseases of the liver.
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Zhang C, Wang C, Li Y, Miwa T, Liu C, Cui W, Song WC, Du J. Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking. Nat Commun 2017; 8:2078. [PMID: 29233958 PMCID: PMC5727192 DOI: 10.1038/s41467-017-01526-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 09/25/2017] [Indexed: 12/20/2022] Open
Abstract
Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb, a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration. Monocytes from C3aR-deficient mice express a reduced level of adhesion molecules, cytokines and genes associated with antigen processing and presentation. Exogenous administration of recombinant CCL5 to C3aR-deficient mice rescues the defects in inflammatory cell recruitment and regeneration. These findings reveal an important role of complement C3a in skeletal muscle regeneration, and suggest that manipulating complement system may produce therapeutic benefit in muscle injury and regeneration.
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Affiliation(s)
- Congcong Zhang
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
| | - Chunxiao Wang
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
| | - Yulin Li
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
| | - Takashi Miwa
- Department of Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Chang Liu
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
| | - Wei Cui
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China
| | - Wen-Chao Song
- Department of Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19104, USA.
| | - Jie Du
- Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
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Jane-Wit D, Fang C, Goldstein DR. Innate immune mechanisms in transplant allograft vasculopathy. Curr Opin Organ Transplant 2017; 21:253-7. [PMID: 27077602 DOI: 10.1097/mot.0000000000000314] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Allograft vasculopathy is the leading cause of late allograft loss following solid organ transplantation. Ischemia reperfusion injury and donor-specific antibody-induced complement activation confer heightened risk for allograft vasculopathy via numerous innate immune mechanisms, including MyD88, high-mobility group box 1 (HMGB1), and complement-induced noncanonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. RECENT FINDINGS The role of MyD88, a signal adaptor downstream of the Toll-like receptors (TLR), has been defined in an experimental heart transplant model, which demonstrated that recipient MyD88 enhanced allograft vasculopathy. Importantly, triggering receptor on myeloid receptor 1, a MyD88 amplifying signal, was present in rejecting human cardiac transplant biopsies and enhanced the development of allograft vasculopathy in mice. HMGB1, a nuclear protein that activates Toll-like receptors, also enhanced the development of allograft vasculopathy. Complement activation elicits assembly of membrane attack complexes on endothelial cells which activate noncanonical NF-κB signaling, a novel complement effector pathway that induces proinflammatory genes and potentiates endothelial cell-mediated alloimmune T-cell activation, processes which enhance allograft vasculopathy. SUMMARY Innate immune mediators, including HMGB1, MyD88, and noncanonical NF-κB signaling via complement activation contribute to allograft vasculopathy. These pathways represent potential therapeutic targets to reduce allograft vasculopathy after solid organ transplantation.
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Affiliation(s)
- Dan Jane-Wit
- aDepartment of Cardiovascular Medicine bDepartment of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA
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Tao Y, Wang M, Chen E, Tang H. Liver Regeneration: Analysis of the Main Relevant Signaling Molecules. Mediators Inflamm 2017; 2017:4256352. [PMID: 28947857 PMCID: PMC5602614 DOI: 10.1155/2017/4256352] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/19/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration includes three phases: priming stage, proliferative phase, and termination phase. The initial step aims to induce hepatocytes to be sensitive to growth factors with the aid of some cytokines, including TNF-α and IL-6. The proliferation phase promotes hepatocytes to re-enter G1 with the stimulation of growth factors. While during the termination stage, hepatocytes will discontinue to proliferate to maintain normal liver mass and function. Except for cytokine- and growth factor-mediated pathways involved in regulating liver regeneration, new substances and technologies emerge to influence the regenerative process. Here, we reviewed novel and important signaling molecules involved in the process of liver regeneration to provide a cue for further research.
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Affiliation(s)
- Yachao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Menglan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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48
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Alawieh A, Tomlinson S. Injury site-specific targeting of complement inhibitors for treating stroke. Immunol Rev 2017; 274:270-280. [PMID: 27782326 DOI: 10.1111/imr.12470] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cumulative evidence indicates a role for the complement system in both pathology and recovery after ischemic stroke. Here, we review the current understanding of the dual role of complement in poststroke injury and recovery, and discuss the challenges of anti-complement therapies. Most complement directed therapeutics currently under investigation or development systemically inhibit the complement system, but since complement is important for immune surveillance and is involved in various homeostatic activities, there are potential risks associated with systemic inhibition. Depending on the target within the complement pathway, other concerns are high concentrations of inhibitor required, low efficacy and poor bioavailability. To overcome these limitations, approaches to target complement inhibitors to specific sites have been investigated. Here, we discuss targeting strategies, with a focus on strategies developed in our lab, to specifically localize complement inhibition to sites of tissue injury and complement activation, and in particular to the postischemic brain. We discuss various injury site-specific targeted complement inhibitors as potential therapeutic agents for the treatment of ischemic stroke treatment, as well as their use as investigative tools for probing complement-dependent pathophysiological processes.
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Affiliation(s)
- Ali Alawieh
- Medical Scientist Training Program, Medical University of South Carolina, Charleston, SC, USA.,Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC, USA. .,Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC, USA.
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Liao JH, Li CC, Wu SH, Fan JW, Gu HT, Wang ZW. Gene Variations of Sixth Complement Component Affecting Tacrolimus Metabolism in Patients with Liver Transplantation for Hepatocellular Carcinoma. Chin Med J (Engl) 2017; 130:1670-1676. [PMID: 28685716 PMCID: PMC5520553 DOI: 10.4103/0366-6999.209886] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Orthotopic liver transplantation (OLT) improves the prognosis of patients with hepatocellular carcinoma (HCC). Moreover, the complement system is a powerful immune effector that can affect liver function and process of liver cirrhosis. However, studies correlating the complement system with tacrolimus metabolism after OLT are scarce. In this study, the role of single nucleotide polymorphisms (SNPs) associated with the sixth complement component (C6) in tacrolimus metabolism was investigated during the early stages of liver transplantation. METHODS The study enrolled 135 adult patients treated with OLT for HCC between August 2011 and October 2013. Ten SNPs in C6 gene and rs776746 in cytochrome P450 3A5 (CYP3A5) gene were investigated. The tacrolimus levels were monitored daily during 4 weeks after transplantation. RESULTS Both donor and recipient CYP3A5 rs776746 allele A were correlated with decreased concentration/dose (C/D) ratios. Recipient C6 rs9200 allele G and donor C6 rs10052999 homozygotes were correlated with lower C/D ratios. Recipient CYP3A5 rs776746 allele A (yielded median tacrolimus C/D ratios of 225.90 at week 1 and 123.61 at week 2), C6 rs9200 allele G (exhibited median tacrolimus C/D ratios of 211.31 at week 1, 110.23 at week 2, and 99.88 at week 3), and donor CYP3A5 rs776746 allele A (exhibited median C/D ratios of 210.82 at week 1, 111.06 at week 2, 77.49 at week 3, and 85.60 at week 4) and C6 rs10052999 homozygote (exhibited median C/D ratios of 167.59 at week 2, 157.99 at week 3, and 155.36 at week 4) were associated with rapid tacrolimus metabolism. With increasing number of these alleles, patients were found to have lower tacrolimus C/D ratios at various time points during the 4 weeks after transplantation. In multiple linear regression analysis, recipient C6 rs9200 group (AA vs. GG/GA) was found to be related to tacrolimus metabolism at weeks 1, 2, and 3 (P = 0.005, P = 0.045, and P = 0.033, respectively), whereas donor C6 rs10052999 group (CC/TT vs. TC) was demonstrated to be correlated with tacrolimus metabolism only at week 4 (P = 0.001). CONCLUSIONS Recipient C6 gene rs9200 polymorphism and donor C6 gene rs10052999 polymorphism are new genetic loci that affect tacrolimus metabolism in patients with HCC after OLT.
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Affiliation(s)
- Jian-Hua Liao
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Chang-Can Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Shao-Han Wu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jun-Wei Fan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Hai-Tao Gu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zhao-Wen Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. Naunyn Schmiedebergs Arch Pharmacol 2017; 390:871-881. [DOI: 10.1007/s00210-017-1389-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
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