|
1
|
Téllez Garcia JM, Steenvoorden T, Bemelman F, Hilhorst M, Tammaro A, Vogt L. Purinoreceptor P2X7 in Extracellular ATP-Mediated Inflammation through the Spectrum of Kidney Diseases and Kidney Transplantation. J Am Soc Nephrol 2025:00001751-990000000-00602. [PMID: 40152923 DOI: 10.1681/asn.0000000711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/24/2025] [Indexed: 03/30/2025] Open
Abstract
Extracellular purines not only play a critical role in maintaining a balanced inflammatory response but may also trigger disproportionate inflammation in various kidney pathologies. Extracellular ATP is the most well-characterized inflammatory purine, which serves as a potent extracellular danger-associated molecular pattern ( i.e ., danger-associated molecular pattern). It signals through the P2 purinoreceptors during both acute and chronic kidney damage. The purinoreceptor P2X7 (P2X7R) has been extensively studied in kidney disease because of its potent ability to enhance inflammation by activating the nucleotide-binding oligomerization domain, leucine rich repeat family pyrin domain containing 3 inflammasome in both immune and parenchymal tubular cells and potential role in immunometabolic reprogramming. We will explore how, following a primary insult to the kidney, disturbance of purinergic balance characterized by extracellular ATP-mediated P2X7R activation exacerbates AKI. Second, we will describe how persistent purinergic disbalance promotes a P2X7R-mediated protracted inflammatory reaction leading to the progression of CKD of different etiologies. Finally, we will also highlight the relevant and emerging role of P2X7R signaling in both antigen-presenting cells and adaptive immune cells to modulate cellular and humoral immune responses in kidney transplantation and hypertension. This review underscores that ATP-P2X7R axis is a key driver of pathologic purinergic signaling, representing a largely unexplored but highly promising clinical target against a wide spectrum of kidney diseases.
Collapse
Affiliation(s)
- Juan Miguel Téllez Garcia
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, The Netherlands
| | - Thei Steenvoorden
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Frederike Bemelman
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Marc Hilhorst
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Alessandra Tammaro
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, The Netherlands
- Department of Pathology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Liffert Vogt
- Department of Internal Medicine Nephrology Section, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| |
Collapse
|
|
2
|
Yu Y, Bi Z, Jiang Q, Huang S, He Y, Gai J, Huang H, Liu L, Gao Y, Li X, Wang C, Wu C. Oxidized ATP Suppresses B Lymphocyte Activity to Attenuate Antibody-mediated Rejection of Kidney Allografts in Mice. Transplantation 2025; 109:e11-e21. [PMID: 38946027 PMCID: PMC11627330 DOI: 10.1097/tp.0000000000005118] [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] [Received: 07/18/2023] [Revised: 05/01/2024] [Accepted: 05/08/2024] [Indexed: 07/02/2024]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) is a major cause of renal allograft dysfunction and loss. Targeting B cells and/or donor-specific antibody removal using plasma exchange and anti-CD20 antibodies are increasingly used in clinical practice, but the efficacy remains limited. Recent studies suggest that targeting purinergic P2X7 receptor/ATP axis can have profound immune regulatory effects in transplant models, but the mechanisms involved remain incompletely defined. METHODS Purified B cells were isolated from the spleen of Balb/C mice and cultured with oxidized ATP at different concentrations. Proliferation and differentiation of B cells were examined. Effects of oxidized ATP were examined in a presensitized animal model where kidney allograft rejection mimics aspects of clinical AMR. Histopathology was assessed at the time of rejection or on day 5 after kidney transplantation. Infiltrating immune cells in renal allografts were detected by flow cytometry. RESULTS Oxidized ATP inhibited B-cell activation and proliferation in vitro, significantly attenuated histological signs of graft injury and prolonged kidney allograft survival. Mechanistically, oxidized ATP inhibited antibody secretion by activated B cells in response to lipopolysaccharide stimulation and markedly suppressed the production of donor-specific antibody in kidney allograft recipients. Oxidized ATP also reduced graft infiltration by other inflammatory cells. CONCLUSIONS These findings provide evidence for the involvement of the purinergic P2X7 receptor pathway in AMR and suggest that targeting this pathways may have important clinical implications.
Collapse
Affiliation(s)
- Yi Yu
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Organ Transplant Center, Zhongshan People’s Hospital, Zhongshan, China
| | - Zirong Bi
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qifeng Jiang
- Department of Pathology, Guangzhou Huayin Medical Laboratory Center, Guangzhou, China
| | - Shangjin Huang
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yingzhen He
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingci Gai
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huiting Huang
- Guangdong Provincial Key Laboratory on Organ Medicine, Guangzhou, China
| | - Longshan Liu
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xirui Li
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Changxi Wang
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Chenglin Wu
- Department of Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory on Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| |
Collapse
|
|
3
|
Gonzalez-Sanchez FA, Sanchez-Huerta TM, Huerta-Gonzalez A, Sepulveda-Villegas M, Altamirano J, Aguilar-Aleman JP, Garcia-Varela R. Diabetes current and future translatable therapies. Endocrine 2024; 86:865-881. [PMID: 38971945 DOI: 10.1007/s12020-024-03944-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/23/2024] [Indexed: 07/08/2024]
Abstract
Diabetes is one of the major diseases and concerns of public health systems that affects over 200 million patients worldwide. It is estimated that 90% of these patients suffer from diabetes type 2, while 10% present diabetes type 1. This type of diabetes and certain types of diabetes type 2, are characterized by dysregulation of blood glycemic levels due to the total or partial depletion of insulin-secreting pancreatic β-cells. Different approaches have been proposed for long-term treatment of insulin-dependent patients; amongst them, cell-based approaches have been the subject of basic and clinical research since they allow blood glucose level sensing and in situ insulin secretion. The current gold standard for insulin-dependent patients is on-demand exogenous insulin application; cell-based therapies aim to remove this burden from the patient and caregivers. In recent years, protocols to isolate and implant pancreatic islets from diseased donors have been developed and tested in clinical trials. Nevertheless, the shortage of donors, along with the need of immunosuppressive companion therapies, have pushed researchers to focus their attention and efforts to overcome these disadvantages and develop alternative strategies. This review discusses current tested clinical approaches and future potential alternatives for diabetes type 1, and some diabetes type 2, insulin-dependent patients. Additionally, advantages and disadvantages of these discussed methods.
Collapse
Affiliation(s)
- Fabio Antonio Gonzalez-Sanchez
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Triana Mayra Sanchez-Huerta
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Alexandra Huerta-Gonzalez
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Maricruz Sepulveda-Villegas
- Departamento de Medicina Genómica y Hepatología, Hospital Civil de Guadalajara, "Fray Antonio Alcalde", Guadalajara, 44280, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44100, Jalisco, Mexico
| | - Julio Altamirano
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Epigmenio González 500, San Pablo, 76130, Santiago de Queretaro, Qro, México
| | - Juan Pablo Aguilar-Aleman
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Ingenieria Biomedica, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México
| | - Rebeca Garcia-Varela
- Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Departamento de Bioingeniería y Biotecnología, Av. General Ramon Corona No 2514, Colonia Nuevo Mexico, CP 45201, Zapopan, Jalisco, México.
- Carbone Cancer Center, University of Wisconsin - Madison, 1111 Highland Ave, Wisconsin, 53705, Madison, USA.
| |
Collapse
|
|
4
|
Sun R, Wang N, Zheng S, Wang H, Xie H. Nanotechnology-based Strategies for Molecular Imaging, Diagnosis, and Therapy of Organ Transplantation. Transplantation 2024; 108:1730-1748. [PMID: 39042368 DOI: 10.1097/tp.0000000000004913] [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: 07/24/2024]
Abstract
Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection.
Collapse
Affiliation(s)
- Ruiqi Sun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Zhejiang Province, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Province, Hangzhou, China
| | - Ning Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Zhejiang Province, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Province, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Zhejiang Province, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Province, Hangzhou, China
| | - Hangxiang Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Zhejiang Province, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Province, Hangzhou, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China
- NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Zhejiang Province, Hangzhou, China
- Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang Province, Hangzhou, China
| |
Collapse
|
|
5
|
Fotino C, Molano RD, Ben Nasr M, Umland O, Fraker CA, Ulissi U, Balasubramanian HB, Lunati ME, Usuelli V, Seelam AJ, Khalefa SA, La Sala C, Gimeno J, Mendez AJ, Ricordi C, Bayer AL, Fiorina P, Pileggi A. Reversal of Experimental Autoimmune Diabetes With an sCD39/Anti-CD3 Treatment. Diabetes 2023; 72:1641-1651. [PMID: 37625134 PMCID: PMC10588287 DOI: 10.2337/db23-0178] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023]
Abstract
Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes. We then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NOD mice compared with prediabetic NOD mice. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T cells. Importantly, prediabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pancreatic lymph nodes, and spleens. The administration of sCD39 into prediabetic NOD mice reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T cells, and increased the frequency of regulatory T cells, while delaying the onset of T1D. Notably, concomitant administration of sCD39 and anti-CD3 showed a strong synergism in restoring normoglycemia in newly hyperglycemic NOD mice compared with monotherapy with anti-CD3 or with sCD39. The eATP/CD39 pathway plays an important role in the onset of T1D, and its targeting might represent a potential therapeutic strategy in T1D. ARTICLE HIGHLIGHTS
Collapse
MESH Headings
- Animals
- Female
- Mice
- 5'-Nucleotidase/metabolism
- Adenosine Triphosphate/metabolism
- Antigens, CD/metabolism
- Apyrase/metabolism
- CD3 Complex/metabolism
- CD3 Complex/immunology
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/metabolism
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism
- Mice, Inbred NOD
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/metabolism
Collapse
Affiliation(s)
- Carmen Fotino
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - R. Damaris Molano
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Oliver Umland
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - Christopher A. Fraker
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
- Division of Cellular Transplantation, DeWitt Daughtry Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
| | - Ulisse Ulissi
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - Hari Baskar Balasubramanian
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Maria Elena Lunati
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Salma Ayman Khalefa
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
| | - Christian La Sala
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - Jennifer Gimeno
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
| | - Armando J. Mendez
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
- Division of Cellular Transplantation, DeWitt Daughtry Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
- Division of Cellular Transplantation, DeWitt Daughtry Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
- Division of Endocrinology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL
- Department of Biomedical Engineering, University of Miami, Miami, FL
| | - Allison L. Bayer
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center “Romeo ed Enrica Invernizzi,” Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA
- Division of Endocrinology, Azienda Socio-Sanitaria Territoriale (ASST) Fatebenefratelli-Sacco, Milan, Italy
| | - Antonello Pileggi
- Cell Transplant Center, Diabetes Research Institute, University of Miami, Miami, FL
- Division of Cellular Transplantation, DeWitt Daughtry Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL
- Department of Biomedical Engineering, University of Miami, Miami, FL
| |
Collapse
|
|
6
|
Kahan R, Cray PL, Abraham N, Gao Q, Hartwig MG, Pollara JJ, Barbas AS. Sterile inflammation in liver transplantation. Front Med (Lausanne) 2023; 10:1223224. [PMID: 37636574 PMCID: PMC10449546 DOI: 10.3389/fmed.2023.1223224] [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: 05/15/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
Sterile inflammation is the immune response to damage-associated molecular patterns (DAMPs) released during cell death in the absence of foreign pathogens. In the setting of solid organ transplantation, ischemia-reperfusion injury results in mitochondria-mediated production of reactive oxygen and nitrogen species that are a major cause of uncontrolled cell death and release of various DAMPs from the graft tissue. When properly regulated, the immune response initiated by DAMP-sensing serves as means of damage control and is necessary for initiation of recovery pathways and re-establishment of homeostasis. In contrast, a dysregulated or overt sterile inflammatory response can inadvertently lead to further injury through recruitment of immune cells, innate immune cell activation, and sensitization of the adaptive immune system. In liver transplantation, sterile inflammation may manifest as early graft dysfunction, acute graft failure, or increased risk of immunosuppression-resistant rejection. Understanding the mechanisms of the development of sterile inflammation in the setting of liver transplantation is crucial for finding reliable biomarkers that predict graft function, and for development of therapeutic approaches to improve long-term transplant outcomes. Here, we discuss the recent advances that have been made to elucidate the early signs of sterile inflammation and extent of damage from it. We also discuss new therapeutics that may be effective in quelling the detrimental effects of sterile inflammation.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Andrew S. Barbas
- Duke Ex-Vivo Organ Lab (DEVOL)—Division of Abdominal Transplant Surgery, Duke University, Durham, NC, United States
| |
Collapse
|
|
7
|
Loretelli C, Pastore I, Lunati ME, Abdelsalam A, Usuelli V, Assi E, Fiorina E, Loreggian L, Balasubramanian HB, Xie Y, Yang J, El Essawy B, Montefusco L, D'Addio F, Ben Nasr M, Fiorina P. eATP and autoimmune diabetes. Pharmacol Res 2023; 190:106709. [PMID: 36842542 DOI: 10.1016/j.phrs.2023.106709] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 02/26/2023]
Abstract
PURPOSE OF REVIEW The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). RECENT FINDINGS T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. SUMMARY In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity.
Collapse
Affiliation(s)
- Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Ahmed Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Emma Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Lara Loreggian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Hari Baskar Balasubramanian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy
| | - Yanan Xie
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Yang
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China; NHC Key Laboratory of Organ Transplantation, Wuhan, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Basset El Essawy
- Medicine, Al-Azhar University, Cairo, Egypt; Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science, Università di Milano, Milan, Italy; Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
8
|
P2 Receptors: Novel Disease Markers and Metabolic Checkpoints in Immune Cells. Biomolecules 2022; 12:biom12070983. [PMID: 35883539 PMCID: PMC9313346 DOI: 10.3390/biom12070983] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/24/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023] Open
Abstract
Extracellular ATP (eATP) and P2 receptors are novel emerging regulators of T-lymphocyte responses. Cellular ATP is released via multiple pathways and accumulates at sites of tissue damage and inflammation. P2 receptor expression and function are affected by numerous single nucleotide polymorphisms (SNPs) associated with diverse disease conditions. Stimulation by released nucleotides (purinergic signalling) modulates several T-lymphocyte functions, among which energy metabolism. Energy metabolism, whether oxidative or glycolytic, in turn deeply affects T-cell activation, differentiation and effector responses. Specific P2R subtypes, among which the P2X7 receptor (P2X7R), are either up- or down-regulated during T-cell activation and differentiation; thus, they can be considered indexes of activation/quiescence, reporters of T-cell metabolic status and, in principle, markers of immune-mediated disease conditions.
Collapse
|
|
9
|
Differentiation of multipotent stem cells to insulin-producing cells for treatment of diabetes mellitus: bone marrow- and adipose tissue-derived cells comparison. Mol Biol Rep 2022; 49:3539-3548. [PMID: 35107740 DOI: 10.1007/s11033-022-07194-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 01/25/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) from human adipose tissue and bone marrow have a great potential for use in cell therapy due to their ease of isolation, expansion, and differentiation. Our intention was to isolate and promote in vitro expansion and differentiation of MSCs from human adipose and bone marrow tissue into cells with a pancreatic endocrine phenotype and to compare the potency of these cells together. METHODS AND RESULTS MSCs were pre-induced with nicotinamide, mercaptoethanol, B-27 and b-FGF in L-DMEM for 2 days and re-induced again in supplemented H-DMEM for another 3 days. Expression of five genes in differentiated beta cells was evaluated by Real-time PCR and western blotting and the potency of insulin release in response to glucose stimulation was evaluated by insulin and C-peptide ELISA kit. The differentiated cells were evaluated by immunocytochemistry staining for Insulin and PDX-1. Quantitative RT-PCR results showed up-regulation of four genes in differentiated beta-islet cells (Insulin, Ngn-3, Pax-4 and Pdx-1) compared with the control. Western blot analysis showed that MSCs cells mainly produced proinsulin and insulin after differentiation but nestin was more expressed in pre-differentiated stem cells. Glucose and insulin secretion assay showed that insulin levels and C-peptide secretion were significantly increased in response to 10 mM glucose. CONCLUSIONS Our study showed that both adipose and bone marrow stem cells could differentiate into functional beta-islet cells but it seems that adipose stem cells could be a better choice for treatment of diabetes mellitus according to their higher potency.
Collapse
|
|
10
|
Mesto N, Movassat J, Tourrel-Cuzin C. P2-type purinergic signaling in the regulation of pancreatic β-cell functional plasticity as a promising novel therapeutic approach for the treatment of type 2 diabetes? Front Endocrinol (Lausanne) 2022; 13:1099152. [PMID: 37065173 PMCID: PMC10099247 DOI: 10.3389/fendo.2022.1099152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
Diabetes Mellitus is a metabolic disorder characterized by a chronic hyperglycemia due to an impaired insulin secretion and a decreased in peripheral insulin sensitivity. This disease is a major public health problem due to it sharp prevalence. Therefore, it is crucial to readapt therapeutic approaches for the treatment of this pathology. One of the strategies would be through P2-type purinergic receptors pathway via ATP binding. In addition to its well-known role as an intracellular energy intermediary in numerous biochemical and physiological processes, ATP is also an important extracellular signaling molecule. ATP mediates its effects by binding and activating two classes of P2 purinoreceptors: P2X receptors that are ligand-gated ion channel receptors, existing in seven isoforms (P2X 1 to 7) and P2Y receptors that are G-protein coupled receptors, existing in eight isoforms (P2Y 1/2/4/6/11/12/13/14). These receptors are ubiquitously distributed and involved in numerous physiological processes in several tissues. The concept of purinergic signaling, originally formulated by Geoffrey Burnstock (1929-2020), was also found to mediate various responses in the pancreas. Several studies have shown that P2 receptors are expressed in the endocrine pancreas, notably in β cells, where ATP could modulate their function but also their plasticity and thus play a physiological role in stimulating insulin secretion to face some metabolic demands. In this review, we provide a historical perspective and summarize current knowledge on P2-type purinergic signaling in the regulation of pancreatic β-cell functional plasticity, which would be a promising novel therapeutic approach for the treatment of type 2 diabetes.
Collapse
|
|
11
|
Fan X, Zhang J, Dai Y, Shan K, Xu J. Blockage of P2X7R suppresses Th1/Th17-mediated immune responses and corneal allograft rejection via inhibiting NLRP3 inflammasome activation. Exp Eye Res 2021; 212:108792. [PMID: 34656546 DOI: 10.1016/j.exer.2021.108792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 09/10/2021] [Accepted: 10/11/2021] [Indexed: 01/03/2023]
Abstract
P2X7R is a vital modifier of various inflammatory and immune-related diseases. However, the immunomodulatory effects of P2X7R on corneal allograft rejection remains unknown. Here we showed that P2X7R expression was significantly upregulated in corneal grafts of allogeneic transplant mice. Pharmacological blockage of P2X7R remarkably prolonged graft survival time, and reduced inflammatory cell infiltration in corneal grafts, in particular Th1/Th17 cells. Meanwhile, the frequencies of Th1/Th17 cells in draining lymph nodes were significantly decreased in P2X7R blocked allogeneic mice. Further results showed that the effect of P2X7R on promoting Th1/Th17 mediated immune responses in corneal allograft rejection relied heavily on its activation on the NLRP3/caspase-1/IL-1β axis, while P2X7R blockage could mitigate such activation. Nevertheless, the addition of IL-1β in vivo abrogated the protective effect of P2X7R blockage on promoting corneal graft survival. These findings demonstrate that blockage of P2X7R can substantially alleviate corneal allograft rejection and promote grafts survival, highlighting it as a promising target for preventing or treating corneal allograft rejection.
Collapse
Affiliation(s)
- Xiangyu Fan
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
| | - Jing Zhang
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, 200031, China
| | - Yiqin Dai
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, 200031, China
| | - Kun Shan
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
| | - Jianjiang Xu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, China; NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, 200031, China.
| |
Collapse
|
|
12
|
Usuelli V, Ben Nasr M, D'Addio F, Liu K, Vergani A, El Essawy B, Yang J, Assi E, Uehara M, Rossi C, Solini A, Capobianco A, Rigamonti E, Potena L, Venturini M, Sabatino M, Bottarelli L, Ammirati E, Frigerio M, Castillo‐Leon E, Maestroni A, Azzoni C, Loretelli C, Joe Seelam A, Tai AK, Pastore I, Becchi G, Corradi D, Visner GA, Zuccotti GV, Chau NB, Abdi R, Pezzolesi MG, Fiorina P. miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy. Am J Transplant 2021; 21:3280-3295. [PMID: 33764625 PMCID: PMC8518036 DOI: 10.1111/ajt.16581] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/19/2021] [Accepted: 03/09/2021] [Indexed: 01/25/2023]
Abstract
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
Collapse
Affiliation(s)
- Vera Usuelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Moufida Ben Nasr
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Francesca D'Addio
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Kaifeng Liu
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Andrea Vergani
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Basset El Essawy
- Department of MedicineAl‐Azhar UniversityCairoEgypt,Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Jun Yang
- Institute of Organ TransplantationTongji Hospital and Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Emma Assi
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Mayuko Uehara
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Chiara Rossi
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Anna Solini
- Department of SurgicalMedical, Molecular and Critical Area PathologyUniversity of PisaPisaItaly
| | - Annalisa Capobianco
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Elena Rigamonti
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Luciano Potena
- Heart Failure and Heart Transplant ProgramS. Orsola‐Malpighi HospitalAlma‐Mater University of BolognaBolognaItaly
| | | | - Mario Sabatino
- Department of Cardiothoracic, Transplantation and Vascular SurgeryS. Orsola‐Malpighi HospitalAlma Mater‐University of BolognaBolognaItaly
| | | | - Enrico Ammirati
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Maria Frigerio
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Eduardo Castillo‐Leon
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Anna Maestroni
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Cinzia Azzoni
- Department of Medicine and SurgeryUniversity of ParmaParmaItaly
| | - Cristian Loretelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Andy Joe Seelam
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Albert K. Tai
- Tufts University Core Facility (TUCF) Genomics CoreTufts University School of MedicineBostonMassachusetts
| | - Ida Pastore
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| | | | | | - Gary A. Visner
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Gian V. Zuccotti
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Department of PediatricsBuzzi Children's HospitalMilanItaly
| | | | - Reza Abdi
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Marcus G. Pezzolesi
- Division of Nephrology and Hypertension, Diabetes and Metabolism CenterUniversity of UtahSalt Lake CityUtah
| | - Paolo Fiorina
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts,Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| |
Collapse
|
|
13
|
Drill M, Jones NC, Hunn M, O'Brien TJ, Monif M. Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer. Purinergic Signal 2021; 17:215-227. [PMID: 33728582 PMCID: PMC8155177 DOI: 10.1007/s11302-021-09776-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.
Collapse
Affiliation(s)
- Matthew Drill
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Physiology, Melbourne University, Parkville, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Nigel C Jones
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Martin Hunn
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurosurgery, Alfred Hospital, Melbourne, VIC, Australia
| | - Terence J O'Brien
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia
| | - Mastura Monif
- Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia.
- Department of Physiology, Melbourne University, Parkville, VIC, Australia.
- Department of Neurology, Alfred Health, Melbourne, VIC, Australia.
- Department of Neurology, Melbourne Health, Parkville, VIC, Australia.
| |
Collapse
|
|
14
|
eATP/P2X7R Axis: An Orchestrated Pathway Triggering Inflammasome Activation in Muscle Diseases. Int J Mol Sci 2020; 21:ijms21175963. [PMID: 32825102 PMCID: PMC7504480 DOI: 10.3390/ijms21175963] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
In muscle ATP is primarily known for its function as an energy source and as a mediator of the "excitation-transcription" process, which guarantees muscle plasticity in response to environmental stimuli. When quickly released in massive concentrations in the extracellular space as in presence of muscle membrane damage, ATP acts as a damage-associated molecular pattern molecule (DAMP). In experimental murine models of muscular dystrophies characterized by membrane instability, blockade of eATP/P2X7 receptor (R) purinergic signaling delayed the progression of the dystrophic phenotype dampening the local inflammatory response and inducing Foxp3+ T Regulatory lymphocytes. These discoveries highlighted the relevance of ATP as a harbinger of immune-tissue damage in muscular genetic diseases. Given the interactions between the immune system and muscle regeneration, the comprehension of ATP/purinerigic pathway articulated organization in muscle cells has become of extreme interest. This review explores ATP release, metabolism, feedback control and cross-talk with members of muscle inflammasome in the context of muscular dystrophies.
Collapse
|
|
15
|
Increased P2X7 expression in the gastrointestinal tract and skin in a humanised mouse model of graft-versus-host disease. Clin Sci (Lond) 2020; 134:207-223. [PMID: 31934722 DOI: 10.1042/cs20191086] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/20/2019] [Accepted: 01/14/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for blood cancers; but results in the development of graft-versus-host disease (GVHD) in up to 70% of recipients. During GVHD, tissue damage results in ATP release into the extracellular compartment activating P2X7 on antigen-presenting cells, leading to the release of pro-inflammatory cytokines and subsequent activation of donor T cells. Therefore, the aim of the present study was to examine murine (m) P2rx7 and human (h) P2RX7 gene expression in GVHD target organs of humanised mice, and further characterise disease impact in these organs. METHODS NOD-scid IL2Rγnull (NSG) mice were injected with human peripheral blood mononuclear cells (hu-PBMC-NSG mice) or phosphate-buffered saline (PBS, control). Leucocytes were assessed by flow cytometry; gene expression was measured by quantitative polymerase chain reaction (qPCR), and tissue sections examined by histology. RESULTS Compared with control mice, hu-PBMC-NSG mice had increased mP2rx7 and mP2rx4 expression in the duodenum, ileum and skin. hP2RX7 was expressed in all tissues examined. hu-PBMC-NSG mice also displayed increased mReg3g expression in the duodenum and ileum, despite limited histological gut GVHD. hu-PBMC-NSG mice showed histological evidence of GVHD in the skin, liver and lung. Compared with control mice, hu-PBMC-NSG mice displayed increased ear swelling. CONCLUSION Combined data revealed that P2rx7 is up-regulated in gut and skin GVHD and that P2RX7 is present in target tissues of GVHD, corresponding to human leucocyte infiltration. Data also reveal increased mReg3g expression and ear swelling in hu-PBMC-NSG mice, offering new measurements of early-stage gut GVHD and skin GVHD, respectively.
Collapse
|
|
16
|
Rivas-Yáñez E, Barrera-Avalos C, Parra-Tello B, Briceño P, Rosemblatt MV, Saavedra-Almarza J, Rosemblatt M, Acuña-Castillo C, Bono MR, Sauma D. P2X7 Receptor at the Crossroads of T Cell Fate. Int J Mol Sci 2020; 21:E4937. [PMID: 32668623 PMCID: PMC7404255 DOI: 10.3390/ijms21144937] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/26/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
The P2X7 receptor is a ligand-gated, cation-selective channel whose main physiological ligand is ATP. P2X7 receptor activation may also be triggered by ARTC2.2-dependent ADP ribosylation in the presence of extracellular NAD. Upon activation, this receptor induces several responses, including the influx of calcium and sodium ions, phosphatidylserine externalization, the formation of a non-selective membrane pore, and ultimately cell death. P2X7 receptor activation depends on the availability of extracellular nucleotides, whose concentrations are regulated by the action of extracellular nucleotidases such as CD39 and CD38. The P2X7 receptor has been extensively studied in the context of the immune response, and it has been reported to be involved in inflammasome activation, cytokine production, and the migration of different innate immune cells in response to ATP. In adaptive immune responses, the P2X7 receptor has been linked to T cell activation, differentiation, and apoptosis induction. In this review, we will discuss the evidence of the role of the P2X7 receptor on T cell differentiation and in the control of T cell responses in inflammatory conditions.
Collapse
Affiliation(s)
- Elizabeth Rivas-Yáñez
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| | - Carlos Barrera-Avalos
- Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9160000, Chile;
| | - Brian Parra-Tello
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| | - Pedro Briceño
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| | - Mariana V. Rosemblatt
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
| | - Juan Saavedra-Almarza
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| | - Mario Rosemblatt
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile
- Fundación Ciencia & Vida, Santiago 7780272, Chile
| | - Claudio Acuña-Castillo
- Centro de Biotecnología Acuícola, Universidad de Santiago de Chile, Santiago 9160000, Chile
| | - María Rosa Bono
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| | - Daniela Sauma
- Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile; (E.R.-Y.); (B.P.-T.); (P.B.); (M.V.R.); (J.S.-A.); (M.R.)
| |
Collapse
|
|
17
|
Ding X, Wilson NA, Redfield RR, Panzer SE, Verhoven B, Reese SR, Zhong W, Shi L, Burlingham WJ, Denlinger LC, Djamali A. Oxidized-ATP Attenuates Kidney Allograft Rejection By Inhibiting T-Cell, B-Cell, and Macrophage Activity. ACTA ACUST UNITED AC 2020; 1:106-114. [DOI: 10.34067/kid.0000692019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/15/2020] [Indexed: 11/27/2022]
Abstract
BackgroundExtracellular ATP binds to purinergic receptors and promotes inflammatory responses. We tested whether oxidized ATP (oATP), P2X7 receptor antagonist can attenuate acute kidney allograft rejection.MethodsBrown Norway kidney allografts were transplanted into Lewis recipients. Three groups were defined: oATP (n=8), cyclosporine A (n=6), and no treatment (n=8). On day 7, we assessed kidney allograft survival, function, and rejection characteristics. We further determined T-cell, B-cell, and macrophage response to oATP in vivo and in vitro and examined intragraft inflammatory gene transcripts.ResultsKaplan–Meier survival analyses demonstrated significantly better graft survival rates in oATP and CsA groups compared with no treatment (P<0.05). Similarly, serum creatinine (Scr) and BUN levels were significantly lower in oATP and CsA groups (P<0.05). oATP reduced both T cell–mediated rejection and antibody-mediated rejection, inhibited B-cell and T-cell activation, and downregulated intragraft IL-6 mRNA levels (P<0.0001). In vitro, oATP prevented proliferation in mixed lymphocyte reaction assays, and inhibited macrophage P2X7R activity in a dose-dependent manner.ConclusionsOur findings suggest that oATP mitigates kidney allograft rejection by inhibiting T-cell, B-cell, and macrophage activity and indicate a potential role for the purinergic system and oATP in solid organ transplantation.
Collapse
|
|
18
|
Abstract
Calcium (Ca2+) signalling is of paramount importance to immunity. Regulated increases in cytosolic and organellar Ca2+ concentrations in lymphocytes control complex and crucial effector functions such as metabolism, proliferation, differentiation, antibody and cytokine secretion and cytotoxicity. Altered Ca2+ regulation in lymphocytes leads to various autoimmune, inflammatory and immunodeficiency syndromes. Several types of plasma membrane and organellar Ca2+-permeable channels are functional in T cells. They contribute highly localized spatial and temporal Ca2+ microdomains that are required for achieving functional specificity. While the mechanistic details of these Ca2+ microdomains are only beginning to emerge, it is evident that through crosstalk, synergy and feedback mechanisms, they fine-tune T cell signalling to match complex immune responses. In this article, we review the expression and function of various Ca2+-permeable channels in the plasma membrane, endoplasmic reticulum, mitochondria and endolysosomes of T cells and their role in shaping immunity and the pathogenesis of immune-mediated diseases.
Collapse
Affiliation(s)
- Mohamed Trebak
- Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
| | - Jean-Pierre Kinet
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
19
|
Tang Z, Ye W, Chen H, Kuang X, Guo J, Xiang M, Peng C, Chen X, Liu H. Role of purines in regulation of metabolic reprogramming. Purinergic Signal 2019; 15:423-438. [PMID: 31493132 DOI: 10.1007/s11302-019-09676-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/28/2019] [Indexed: 12/19/2022] Open
Abstract
Purines, among most influential molecules, are reported to have essential biological function by regulating various cell types. A large number of studies have led to the discovery of many biological functions of the purine nucleotides such as ATP, ADP, and adenosine, as signaling molecules that engage G protein-coupled or ligand-gated ion channel receptors. The role of purines in the regulation of cellular functions at the gene or protein level has been well documented. With the advances in multiomics, including those from metabolomic and bioinformatic analyses, metabolic reprogramming was identified as a key mechanism involved in the regulation of cellular function under physiological or pathological conditions. Recent studies suggest that purines or purine-derived products contribute to important regulatory functions in many fundamental biological and pathological processes related to metabolic reprogramming. Therefore, this review summarizes the role and potential mechanism of purines in the regulation of metabolic reprogramming. In particular, the molecular mechanisms of extracellular purine- and intracellular purine-mediated metabolic regulation in various cells during disease development are discussed. In summary, our review provides an extensive resource for studying the regulatory role of purines in metabolic reprogramming and sheds light on the utilization of the corresponding peptides or proteins for disease diagnosis and therapy.
Collapse
Affiliation(s)
- Zhenwei Tang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Medicine Eight-Year Program, Xiangya Medical School of Central South University, Changsha, Hunan, China
| | - Wenrui Ye
- Clinical Medicine Eight-Year Program, Xiangya Medical School of Central South University, Changsha, Hunan, China
| | - Haotian Chen
- Clinical Medicine Eight-Year Program, Xiangya Medical School of Central South University, Changsha, Hunan, China
| | - Xinwei Kuang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jia Guo
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Minmin Xiang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Hong Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Center for Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| |
Collapse
|
|
20
|
Foulsham W, Mittal SK, Nakao T, Coco G, Taketani Y, Chauhan SK, Dana R. The purinergic receptor antagonist oxidized adenosine triphosphate suppresses immune-mediated corneal allograft rejection. Sci Rep 2019; 9:8617. [PMID: 31197223 PMCID: PMC6565802 DOI: 10.1038/s41598-019-44973-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 05/20/2019] [Indexed: 01/09/2023] Open
Abstract
Adenosine triphosphate (ATP) is released into the extracellular environment during transplantation, and acts via purinergic receptors to amplify the alloimmune response. Here, using a well-established murine model of allogeneic corneal transplantation, we investigated the immunomodulatory mechanisms of the purinergic receptor antagonist oxidized ATP (oATP). Corneal transplantation was performed using C57BL/6 donors and BALB/c hosts. oATP or sterile saline was administered via intraperitoneal injection for 2 weeks postoperatively. Frequencies of CD45+ leukocytes, CD11b+MHCII+ antigen presenting cells (APCs), CD4+IFN-γ+ effector Th1 cells and CD4+Foxp3+ regulatory T cells (Tregs) were evaluated by flow cytometry. Slit-lamp microscopy was performed weekly for 8 weeks to evaluate graft opacity and determine transplant rejection. Treatment with oATP was shown to significantly reduce graft infiltration of CD45+ leukocytes, decrease APC maturation and suppress effector Th1 cell generation relative to saline-treated control. No difference in Treg frequencies or Foxp3 expression was observed between the oATP-treated and control groups. Finally, oATP treatment was shown to reduce graft opacity and increase graft survival. This report demonstrates that oATP limits the alloimmune response by regulating APC maturation and suppressing the generation of alloreactive Th1 immunity.
Collapse
Affiliation(s)
- William Foulsham
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Institute of Ophthalmology, University College London, London, UK
| | - Sharad K Mittal
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Takeshi Nakao
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Giulia Coco
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Yukako Taketani
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Sunil K Chauhan
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
21
|
Abstract
PURPOSE OF REVIEW Purine nucleosides and nucleotides are released in the extracellular space following cell injury and act as paracrine mediators through a number of dedicated membrane receptors. In particular, extracellular ATP (eATP) significantly influences T-lymphocyte activation and phenotype. The purpose of this review is to discuss the role of ATP signaling in the T-cell-mediated alloimmune response. RECENT FINDINGS In various animal models of solid transplantation, the purinergic axis has been targeted to prevent acute rejection and to promote long-term graft tolerance. The inhibition of ATP-gated P2X receptors has been shown to halt lymphocyte activation, to downregulate both Th1 and Th17 responses and to promote T-regulatory (Treg) cell differentiation. Similarly, the inhibition of ATP signaling attenuated graft-versus-host disease in mice undergoing hematopoietic cell transplantation. Significantly, different drugs targeting the purinergic system have been recently approved for human use and may be a viable therapeutic option for transplant patients. SUMMARY The inhibition of eATP signaling downregulates the alloimmune response, expands Treg cells and promotes graft survival. This robust preclinical evidence and the recent advances in pharmacological research may lead to intriguing clinical applications.
Collapse
|
|
22
|
Gazzerro E, Baratto S, Assereto S, Baldassari S, Panicucci C, Raffaghello L, Scudieri P, De Battista D, Fiorillo C, Volpi S, Chaabane L, Malnati M, Messina G, Bruzzone S, Traggiai E, Grassi F, Minetti C, Bruno C. The Danger Signal Extracellular ATP Is Involved in the Immunomediated Damage of α-Sarcoglycan-Deficient Muscular Dystrophy. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:354-369. [PMID: 30448410 DOI: 10.1016/j.ajpath.2018.10.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 09/28/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023]
Abstract
In muscular dystrophies, muscle membrane fragility results in a tissue-specific increase of danger-associated molecular pattern molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular ATP (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the triggering of the immune response and inhibition of regulatory T cells. Accordingly, pharmacologic and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases. In α-sarcoglycanopathy, eATP effects may be further amplified because α-sarcoglycan extracellular domain binds eATP and displays an ecto-ATPase activity, thus controlling eATP concentration at the cell surface and attenuating the magnitude and/or the duration of eATP-induced signals. Herein, we show that in vivo blockade of the eATP/P2X purinergic pathway by a broad-spectrum P2X receptor-antagonist delayed the progression of the dystrophic phenotype in α-sarcoglycan-null mice. eATP blockade dampened the muscular inflammatory response and enhanced the recruitment of forkhead box protein P3-positive immunosuppressive regulatory CD4+ T cells. The improvement of the inflammatory features was associated with increased strength, reduced necrosis, and limited expression of profibrotic factors, suggesting that pharmacologic purinergic antagonism, altering the innate and adaptive immune component in muscle infiltrates, might provide a therapeutic approach to slow disease progression in α-sarcoglycanopathy.
Collapse
Affiliation(s)
- Elisabetta Gazzerro
- Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy; Charité Universität-Experimental and Clinical Research Center, Berlin, Germany.
| | - Serena Baratto
- Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy
| | - Stefania Assereto
- Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy
| | - Simona Baldassari
- Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy
| | - Chiara Panicucci
- Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy
| | - Lizzia Raffaghello
- Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy; Stem Cell Laboratory and Cell Therapy Center, Istituto Giannina Gaslini, Genova, Italy
| | - Paolo Scudieri
- Telethon Institute of Genetics and Medicine, Napoli, Italy
| | - Davide De Battista
- Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy
| | - Chiara Fiorillo
- Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy
| | - Stefano Volpi
- Pediatria II Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Linda Chaabane
- Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy
| | - Mauro Malnati
- Unit of Human Virology, Division of Immunology, Transplantation and Infectious Disease, Ospedale San Raffaele, Milano, Italy
| | | | - Santina Bruzzone
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | | | - Fabio Grassi
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy; Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland; Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
| | - Carlo Minetti
- Pediatric Neurology and Muscle Disease Unit, Istituto Giannina Gaslini, Genova, Italy
| | - Claudio Bruno
- Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy.
| |
Collapse
|
|
23
|
Tezza S, Ben Nasr M, D'Addio F, Vergani A, Usuelli V, Falzoni S, Bassi R, Dellepiane S, Fotino C, Rossi C, Maestroni A, Solini A, Corradi D, Giani E, Mameli C, Bertuzzi F, Pezzolesi MG, Wasserfall CH, Atkinson MA, Füchtbauer EM, Ricordi C, Folli F, Di Virgilio F, Pileggi A, Dhe-Paganon S, Zuccotti GV, Fiorina P. Islet-Derived eATP Fuels Autoreactive CD8 + T Cells and Facilitates the Onset of Type 1 Diabetes. Diabetes 2018; 67:2038-2053. [PMID: 30065030 PMCID: PMC6905486 DOI: 10.2337/db17-1227] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 07/06/2018] [Indexed: 01/13/2023]
Abstract
Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in patients with newly diagnosed T1D, P2X7R is upregulated on CD8+ effector T cells in comparison with healthy control subjects. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8+ T cells in vitro. P2X7R blockade with oxidized ATP reduces the CD8+ T cell-mediated autoimmune response in vitro and delays diabetes onset in NOD mice. Autoreactive CD8+ T-cell activation is highly dependent upon eATP/P2X7R-mediated priming, while a novel sP2X7R recombinant protein abrogates changes in metabolism and the autoimmune response associated with CD8+ T cells. eATP/P2X7R signaling facilitates the onset of autoimmune T1D by fueling autoreactive CD8+ cells and therefore represents a novel targeted therapeutic for the disorder.
Collapse
Affiliation(s)
- Sara Tezza
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Moufida Ben Nasr
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Francesca D'Addio
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Andrea Vergani
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Vera Usuelli
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Simonetta Falzoni
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Roberto Bassi
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Sergio Dellepiane
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Carmen Fotino
- Diabetes Research Institute, University of Miami, FL
| | - Chiara Rossi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Anna Maestroni
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
| | - Anna Solini
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Domenico Corradi
- Pathology and Laboratory Medicine, University of Parma, Parma, Italy
| | - Elisa Giani
- Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Chiara Mameli
- Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Federico Bertuzzi
- Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marcus G Pezzolesi
- Division of Nephrology & Hypertension and Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT
| | - Clive H Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
| | | | | | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, University of Milan, Milan, Italy
- ASST Santi Paolo e Carlo, Ospedali San Paolo e San Carlo Borromeo, Milan, Italy
| | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | | | | | - Gian Vincenzo Zuccotti
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
- Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | - Paolo Fiorina
- Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
- International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| |
Collapse
|
|
24
|
Baroja-Mazo A, Revilla-Nuin B, de Bejar Á, Martínez-Alarcón L, Herrero JI, El-Tayeb A, Müller CE, Aparicio P, Pelegrín P, Pons JA. Extracellular adenosine reversibly inhibits the activation of human regulatory T cells and negatively influences the achievement of the operational tolerance in liver transplantation. Am J Transplant 2018; 19:48-61. [PMID: 30019408 PMCID: PMC6298591 DOI: 10.1111/ajt.15023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/15/2018] [Accepted: 07/10/2018] [Indexed: 01/25/2023]
Abstract
The artificial induction of tolerance in transplantation is gaining strength. In mice, a differential role of extracellular adenosine (eADO) for regulatory and effector T cells (Tregs and Teffs, respectively) has been proposed: inhibiting Teffs and inducing Tregs. The aim of this study was to analyze the action of extracellular nucleotides in human T cells and, moreover, to examine the influence of CD39 and CD73 ectonucleotidases and subsequent adenosine signaling through adenosine 2 receptor (A2 R) in the induction of clinical tolerance after liver transplant. The action of extracellular nucleotides in human T cells was analyzed by in vitro experiments with isolated T cells. Additionally, 17 liver transplant patients were enrolled in an immunosuppression withdrawal trial, and the differences in the CD39-CD73-A2 R axis were compared between tolerant and nontolerant patients. In contrast to the mice, the activation of human Tregs was inhibited similarly to Teffs in the presence of eADO. Moreover, the expression of the enzyme responsible for the degradation of ADO, adenosine deaminase, was higher in tolerant patients with respect to the nontolerant group along the immunosuppression withdrawal. Our data support the idea that eADO signaling and its degradation may play a role in the complex system of regulation of liver transplant tolerance.
Collapse
Affiliation(s)
- Alberto Baroja-Mazo
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain,Corresponding Author: Alberto Baroja-Mazo; Biomedical Research Institute of Murcia-Virgen de la Arrixaca; LAIB Building - Lab 4.20; Ctra. Buenavista s/n 30120 Murcia (SPAIN); +34 868885031;
| | - Beatriz Revilla-Nuin
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain
| | - África de Bejar
- Clinical LaboratoryUnit, Hospital de Denia-Marina Salud, Denia, Spain
| | - Laura Martínez-Alarcón
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain
| | - José I. Herrero
- Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Instituto de Investigación Sanitaria de Navarra (IdiSNA)
| | - Ali El-Tayeb
- Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I. Bonn, Germany
| | - Christa E. Müller
- Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I. Bonn, Germany
| | - Pedro Aparicio
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain,Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, Murcia, Spain
| | - Pablo Pelegrín
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain
| | - José A. Pons
- Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital “Virgen de la Arrixaca”. Murcia, Spain,Division of Gastroenterology and Hepatology and Liver Transplant Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain
| |
Collapse
|
|
25
|
D'Addio F, Vergani A, Potena L, Maestroni A, Usuelli V, Ben Nasr M, Bassi R, Tezza S, Dellepiane S, El Essawy B, Iascone M, Iacovoni A, Borgese L, Liu K, Visner G, Dhe-Paganon S, Corradi D, Abdi R, Starling RC, Folli F, Zuccotti GV, Sayegh MH, Heeger PS, Chandraker A, Grigioni F, Fiorina P. P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes. J Clin Invest 2018; 128:3490-3503. [PMID: 30010623 DOI: 10.1172/jci94524] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 05/23/2018] [Indexed: 12/23/2022] Open
Abstract
Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.
Collapse
Affiliation(s)
- Francesca D'Addio
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Andrea Vergani
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Luciano Potena
- Heart Failure and Heart Transplant Program, Department of Experimental Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna, Italy
| | - Anna Maestroni
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Vera Usuelli
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Moufida Ben Nasr
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Roberto Bassi
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sara Tezza
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Sergio Dellepiane
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Basset El Essawy
- Medicine, Al-Azhar University, Cairo, Egypt.,Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Attilio Iacovoni
- Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Borgese
- Heart Failure and Heart Transplant Program, Department of Experimental Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna, Italy
| | - Kaifeng Liu
- Division of Respiratory Diseases, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Gary Visner
- Division of Respiratory Diseases, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Domenico Corradi
- Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy
| | - Reza Abdi
- Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Randall C Starling
- Heart Failure Center, Heart & Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Franco Folli
- Endocrinology and Metabolism, Department of Health Science, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy
| | - Gian Vincenzo Zuccotti
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.,Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
| | | | - Peter S Heeger
- Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Anil Chandraker
- Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Francesco Grigioni
- Heart Failure and Heart Transplant Program, Department of Experimental Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna, Italy
| | - Paolo Fiorina
- International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Endocrinology Division, ASST Fatebenefratelli Sacco, Milan, Italy
| |
Collapse
|
|
26
|
Tozzi M, Larsen AT, Lange SC, Giannuzzo A, Andersen MN, Novak I. The P2X7 receptor and pannexin-1 are involved in glucose-induced autocrine regulation in β-cells. Sci Rep 2018; 8:8926. [PMID: 29895988 PMCID: PMC5997690 DOI: 10.1038/s41598-018-27281-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 05/31/2018] [Indexed: 01/02/2023] Open
Abstract
Extracellular ATP is an important short-range signaling molecule that promotes various physiological responses virtually in all cell types, including pancreatic β-cells. It is well documented that pancreatic β-cells release ATP through exocytosis of insulin granules upon glucose stimulation. We hypothesized that glucose might stimulate ATP release through other non-vesicular mechanisms. Several purinergic receptors are found in β-cells and there is increasing evidence that purinergic signaling regulates β-cell functions and survival. One of the receptors that may be relevant is the P2X7 receptor, but its detailed role in β-cell physiology is unclear. In this study we investigated roles of the P2X7 receptor and pannexin-1 in ATP release, intracellular ATP, Ca2+ signals, insulin release and cell proliferation/survival in β-cells. Results show that glucose induces rapid release of ATP and significant fraction of release involves the P2X7 receptor and pannexin-1, both expressed in INS-1E cells, rat and mouse β-cells. Furthermore, we provide pharmacological evidence that extracellular ATP, via P2X7 receptor, stimulates Ca2+ transients and cell proliferation in INS-1E cells and insulin secretion in INS-1E cells and rat islets. These data indicate that the P2X7 receptor and pannexin-1 have important functions in β-cell physiology, and should be considered in understanding and treatment of diabetes.
Collapse
Affiliation(s)
- Marco Tozzi
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Anna T Larsen
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Sofie C Lange
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Giannuzzo
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Martin N Andersen
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Ivana Novak
- Section for Cell Biology and Physiology, August Krogh Building, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
27
|
Novak I, Solini A. P2X receptor-ion channels in the inflammatory response in adipose tissue and pancreas — potential triggers in onset of type 2 diabetes? Curr Opin Immunol 2018. [DOI: 10.1016/j.coi.2018.02.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
28
|
The therapeutic potential of purinergic signalling. Biochem Pharmacol 2018; 151:157-165. [DOI: 10.1016/j.bcp.2017.07.016] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 07/18/2017] [Indexed: 01/05/2023]
|
|
29
|
Abstract
Diabetes mellitus is characterized by increased levels of reactive oxygen species (ROS), leading to high levels of adenosine triphosphate (ATP) and the activation of purinergic receptors (P2X7), which results in cell death. Klotho was recently described as a modulator of oxidative stress and as having anti-apoptotic properties, among others. However, the roles of P2X7 and klotho in the progression of diabetic nephropathy are still unclear. In this context, the aim of the present study was to characterize P2X7 and klotho in several stages of diabetes in rats. Diabetes was induced in Wistar rats by streptozotocin, while the control group rats received the drug vehicle. From the 1st to 8th weeks after the diabetes induction, the animals were placed in metabolic cages on the 1st day of each week for 24 h to analyze metabolic parameters and for the urine collection. Then, blood samples and the kidneys were collected for biochemical analysis, including Western blotting and qPCR for P2X7 and klotho. Diabetic rats presented a progressive loss of renal function, with reduced nitric oxide and increased lipid peroxidation. The P2X7 and klotho expressions were similar up to the 4th week; then, P2X7 expression increased in diabetes mellitus (DM), but klotho expression presented an opposite behavior, until the 8th week. Our data show an inverse correlation between P2X7 and klotho expressions through the development of DM, which suggests that the management of these molecules could be useful for controlling the progression of this disease and diabetic nephropathy.
Collapse
|
|
30
|
Burnstock G, Knight GE. The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 2018; 14:1-18. [PMID: 29164451 PMCID: PMC5842154 DOI: 10.1007/s11302-017-9593-0] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/01/2017] [Indexed: 12/22/2022] Open
Abstract
Seven P2X ion channel nucleotide receptor subtypes have been cloned and characterised. P2X7 receptors (P2X7R) are unusual in that there are extra amino acids in the intracellular C terminus. Low concentrations of ATP open cation channels sometimes leading to cell proliferation, whereas high concentrations of ATP open large pores that release inflammatory cytokines and can lead to apoptotic cell death. Since many diseases involve inflammation and immune responses, and the P2X7R regulates inflammation, there has been recent interest in the pathophysiological roles of P2X7R and the potential of P2X7R antagonists to treat a variety of diseases. These include neurodegenerative diseases, psychiatric disorders, epilepsy and a number of diseases of peripheral organs, including the cardiovascular, airways, kidney, liver, bladder, skin and musculoskeletal. The potential of P2X7R drugs to treat tumour progression is discussed.
Collapse
Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK.
- Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia.
- Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Australia.
| | - Gillian E Knight
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK
| |
Collapse
|
|
31
|
Simeonovic CJ, Popp SK, Starrs LM, Brown DJ, Ziolkowski AF, Ludwig B, Bornstein SR, Wilson JD, Pugliese A, Kay TWH, Thomas HE, Loudovaris T, Choong FJ, Freeman C, Parish CR. Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLoS One 2018; 13:e0191360. [PMID: 29415062 PMCID: PMC5802856 DOI: 10.1371/journal.pone.0191360] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 01/03/2018] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.
Collapse
Affiliation(s)
- Charmaine J. Simeonovic
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
- * E-mail:
| | - Sarah K. Popp
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Lora M. Starrs
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Debra J. Brown
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Andrew F. Ziolkowski
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Barbara Ludwig
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - Stefan R. Bornstein
- Department of Internal Medicine III, Carl Gustav Carus Medical School, Technical University of Dresden, Dresden, Germany
| | - J. Dennis Wilson
- Department of Endocrinology, The Canberra Hospital, Woden, Australian Capital Territory, Australia
| | - Alberto Pugliese
- Diabetes Research Institute, Departments of Medicine, Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Thomas W. H. Kay
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Helen E. Thomas
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Thomas Loudovaris
- St Vincent’s Institute of Medical Research, Fitzroy, Melbourne, Victoria, Australia
| | - Fui Jiun Choong
- Department of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Craig Freeman
- Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Christopher R. Parish
- Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| |
Collapse
|
|
32
|
Savio LEB, de Andrade Mello P, da Silva CG, Coutinho-Silva R. The P2X7 Receptor in Inflammatory Diseases: Angel or Demon? Front Pharmacol 2018; 9:52. [PMID: 29467654 PMCID: PMC5808178 DOI: 10.3389/fphar.2018.00052] [Citation(s) in RCA: 312] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors-P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.
Collapse
Affiliation(s)
- Luiz E B Savio
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paola de Andrade Mello
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, United States
| | - Cleide Gonçalves da Silva
- Division of Vascular Surgery, Department of Surgery, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Robson Coutinho-Silva
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
33
|
Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F. The P2X7 receptor: A main player in inflammation. Biochem Pharmacol 2017; 151:234-244. [PMID: 29288626 DOI: 10.1016/j.bcp.2017.12.021] [Citation(s) in RCA: 287] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/22/2017] [Indexed: 12/21/2022]
Abstract
Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7R is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes and their precursors. Here we give an overview of recent and established literature on the role of P2X7R in septic and sterile inflammation. P2X7R ability in restraining intracellular bacteria and parasite infection by modulation of the immune response are described, with particular focus on Mycobacteria and Plasmodium. Emerging literature on the role of P2X7 in viral infections such as HIV-1 is also briefly covered. Finally, we describe the numerous intracellular pathways related to inflammation and activated by the P2X7R, including the NLRP3 inflammasome, NF-kB, NFAT, GSK3β and VEGF, and discuss the involvement of P2X7R in chronic diseases. The possible therapeutic applications of P2X7R antagonists are also described.
Collapse
Affiliation(s)
- Elena Adinolfi
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Anna Lisa Giuliani
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Elena De Marchi
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Anna Pegoraro
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Elisa Orioli
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
| | - Francesco Di Virgilio
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
| |
Collapse
|
|
34
|
Burnstock G. Purinergic Signalling: Therapeutic Developments. Front Pharmacol 2017; 8:661. [PMID: 28993732 PMCID: PMC5622197 DOI: 10.3389/fphar.2017.00661] [Citation(s) in RCA: 292] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 09/05/2017] [Indexed: 12/15/2022] Open
Abstract
Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990's when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson's disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.
Collapse
Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical SchoolLondon, United Kingdom
- Department of Pharmacology and Therapeutics, The University of Melbourne, MelbourneVIC, Australia
| |
Collapse
|
|
35
|
Adenosine Triphosphate Promotes Allergen-Induced Airway Inflammation and Th17 Cell Polarization in Neutrophilic Asthma. J Immunol Res 2017. [PMID: 28626774 PMCID: PMC5463097 DOI: 10.1155/2017/5358647] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Adenosine triphosphate (ATP) is a key mediator to alert the immune dysfunction by acting on P2 receptors. Here, we found that allergen challenge caused an increase of ATP secretion in a murine model of neutrophilic asthma, which correlated well with neutrophil counts and interleukin-17 production. When ATP signaling was blocked by intratracheal administration of the ATP receptor antagonist suramin before challenge, neutrophilic airway inflammation, airway hyperresponsiveness, and Th17-type responses were reduced significantly. Also, neutrophilic inflammation was abrogated when airway ATP levels were locally neutralized using apyrase. Furthermore, ATP promoted the Th17 polarization of splenic CD4+ T cells from DO11.10 mice in vitro. In addition, ovalbumin (OVA) challenge induced neutrophilic inflammation and Th17 polarization in DO11.10 mice, whereas administration of suramin before challenge alleviated these parameters. Thus, ATP may serve as a marker of neutrophilic asthma, and local blockade of ATP signaling might provide an alternative method to prevent Th17-mediated airway inflammation in neutrophilic asthma.
Collapse
|
|
36
|
The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells. Kidney Int 2017; 92:415-431. [PMID: 28396117 DOI: 10.1016/j.kint.2017.01.031] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 01/07/2017] [Accepted: 01/26/2017] [Indexed: 12/12/2022]
Abstract
Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69+CD4+, and CD44+CD4+ T cells was attenuated, but renal Foxp3+CD4+ Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3+CD4+ Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.
Collapse
|
|
37
|
Giraldo JA, Molano RD, Rengifo HR, Fotino C, Gattás-Asfura KM, Pileggi A, Stabler CL. The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model. Acta Biomater 2017; 49:272-283. [PMID: 27915019 DOI: 10.1016/j.actbio.2016.11.060] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 11/22/2016] [Accepted: 11/29/2016] [Indexed: 12/22/2022]
Abstract
Islet transplantation is a promising therapy for Type 1 diabetes mellitus; however, host inflammatory and immune responses lead to islet dysfunction and destruction, despite potent systemic immunosuppression. Grafting of poly(ethylene glycol) (PEG) to the periphery of cells or tissues can mitigate inflammation and immune recognition via generation of a steric barrier. Herein, we sought to evaluate the complementary impact of islet PEGylation with a short-course immunotherapy on the survival of fully-MHC mismatched islet allografts (DBA/2 islets into diabetic C57BL/6J recipients). Anti-Lymphocyte Function-associated Antigen 1 (LFA-1) antibody was selected as a complementary, transient, systemic immune monotherapy. Islets were PEGylated via an optimized protocol, with resulting islets exhibiting robust cell viability and function. Following transplantation, a significant subset of diabetic animals receiving PEGylated islets (60%) or anti-LFA-1 antibody (50%) exhibited long-term (>100d) normoglycemia. The combinatorial approach proved synergistic, with 78% of the grafts exhibiting euglycemia long-term. Additional studies examining graft cellular infiltrates at early time points characterized the local impact of the transplant protocol on graft survival. Results illustrate the capacity of a simple polymer grafting approach to impart significant immunoprotective effects via modulation of the local transplant environment, while short-term immunotherapy serves to complement this effect. STATEMENT OF SIGNIFICANCE We believe this study is important and of interest to the biomaterials and transplant community for several reasons: 1) it provides an optimized protocol for the PEGylation of islets, with minimal impact on the coated islets, which can be easily translated for clinical applications; 2) this optimized protocol demonstrates the benefits of islet PEGylation in providing modest immunosuppression in a murine model; 3) this work demonstrates the combinatory impact of PEGylation with short-course immunotherapy (via LFA-1 blockage), illustrating the capacity of PEGylation to complement existing immunotherapy; and 4) it suggests macrophage phenotype shifting as the potential mechanism for this observed benefit.
Collapse
Affiliation(s)
- Jaime A Giraldo
- Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - R Damaris Molano
- Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA
| | - Hernán R Rengifo
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - Carmen Fotino
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - Kerim M Gattás-Asfura
- Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Antonello Pileggi
- Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA; Department of Microbiology & Immunology, University of Miami, Miami, FL, USA
| | - Cherie L Stabler
- Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA; Department of Microbiology & Immunology, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
| |
Collapse
|
|
38
|
Guardado-Mendoza R, Chávez AO, Jiménez-Ceja LM, Hansis-Diarte A, DeFronzo RA, Folli F, Tripathy D. Islet amyloid polypeptide response to maximal hyperglycemia and arginine is altered in impaired glucose tolerance and type 2 diabetes mellitus. Acta Diabetol 2017; 54:53-61. [PMID: 27624579 DOI: 10.1007/s00592-016-0904-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 08/18/2016] [Indexed: 12/29/2022]
Abstract
AIMS Pancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. METHODS Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus. Acute insulin (AIR), C-peptide (ACPR) and IAPP (AIAR) responses during each hyperglycemic step and following arginine (AIRArg) were assessed. RESULTS AIR and ACPR during both hyperglycemic steps and after arginine progressively decreased from NGT to IGT to T2DM. Fasting IAPP concentrations were higher in T2DM compared to NGT and IGT subjects. The acute IAPP0-10 was markedly decreased only in T2DM, while the acute IAPP80-90 response during the second step (80-160 min) of hyperglycemic clamp and in response to arginine was markedly impaired in both IGT and T2DM. The ratio of IAPP/C-peptide during the first (225 mg/dl) and second step (400 mg/dl), and in response to arginine, was decreased in T2DM versus both NGT and IGT (p < 0.01). The acute IAPP0-10 correlated with ACPR0-10 (r = 0.665, p < 0.001) and AIR0-10 (r = 0.543, p < 0.001). CONCLUSIONS Basal IAPP secretion is higher in T2DM and IGT versus NGT but is reduced in response to hyperglycemia and arginine. The IAPP/C-peptide ratio is reduced with prolonged and more severe hyperglycemia in T2DM individuals. CLINICAL TRIAL REGISTRATION NCT00845182.
Collapse
Affiliation(s)
- Rodolfo Guardado-Mendoza
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
- Division of Health Sciences, Department of Medicine and Nutrition, University of Guanajuato, Guanajuato, Mexico
- Departamento de Investigación, Hospital Regional de Alta Especialidad del Bajío, Guanajuato, Mexico
| | - Alberto O Chávez
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
| | - Lilia M Jiménez-Ceja
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
- Division of Health Sciences, Department of Medicine and Nutrition, University of Guanajuato, Guanajuato, Mexico
- Departamento de Investigación, Hospital Regional de Alta Especialidad del Bajío, Guanajuato, Mexico
| | - Andrea Hansis-Diarte
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
| | - Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
- Audie L Murphy VA Hospital, South Texas Veteran Health Care System, San Antonio, TX, USA
| | - Franco Folli
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA
| | - Devjit Tripathy
- Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229, TX, USA.
- Audie L Murphy VA Hospital, South Texas Veteran Health Care System, San Antonio, TX, USA.
| |
Collapse
|
|
39
|
Gicquel T, Le Daré B, Boichot E, Lagente V. Purinergic receptors: new targets for the treatment of gout and fibrosis. Fundam Clin Pharmacol 2016; 31:136-146. [PMID: 27885718 DOI: 10.1111/fcp.12256] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 11/02/2016] [Accepted: 11/18/2016] [Indexed: 12/11/2022]
Abstract
Adenosine triphosphate is involved in many metabolic reactions, but it has also a role as a cellular danger signal transmitted through purinergic receptors (PRs). Indeed, adenosine 5'-triphosphate (ATP) can bind to PRs which are found in the membrane of many cell types, although the relative proportions of the receptor subtypes differ. PRs are classified according to genetic and pharmacological criteria and especially their affinities for agonists and their transduction mechanism (i.e. as metabotropic P2YRs or ionotropic P2XRs). Extracellular ATP release by activated or necrotic cells may activate various PRs and especially P2X7R, the best-characterized PR, on immune cells. P2X7R is known to regulate the activation of the Nod-like receptor (NLR)-family protein, NLRP3 inflammasome, which permit the release of IL-1β, a potent pro-inflammatory cytokine. The P2X7R/NLRP3 pathway is involved in many inflammatory diseases, such as gout, and in fibrosis diseases associated with inflammatory process, liver or lung fibrosis. Some authors imaging also a real promising therapeutic potential of P2X7R blockage. Thus, several pharmaceutical companies have developed P2X7R antagonists as novel anti-inflammatory drug candidates. Clinical trials of the efficacy of these antagonists are now underway. A better understanding of the P2X7R/NLRP3 signalling pathways permits the identification of targets and the development of a new class of drugs able to inhibit the fibrogenesis process and collagen deposition.
Collapse
Affiliation(s)
- Thomas Gicquel
- Laboratoire de toxicologie biologique et médico-légale, CHU Rennes, F-35033, Rennes, France.,UMR991 INSERM, Faculté de Pharmacie, Université Rennes 1, F-35043, Rennes, France
| | - Brendan Le Daré
- UMR991 INSERM, Faculté de Pharmacie, Université Rennes 1, F-35043, Rennes, France.,CHU Rennes, Pôle Pharmacie, F-35033, Rennes, France
| | - Elisabeth Boichot
- UMR991 INSERM, Faculté de Pharmacie, Université Rennes 1, F-35043, Rennes, France
| | - Vincent Lagente
- UMR991 INSERM, Faculté de Pharmacie, Université Rennes 1, F-35043, Rennes, France
| |
Collapse
|
|
40
|
Zhang PA, Xu QY, Xue L, Zheng H, Yan J, Xiao Y, Xu GY. Neonatal Maternal Deprivation Enhances Presynaptic P2X7 Receptor Transmission in Insular Cortex in an Adult Rat Model of Visceral Hypersensitivity. CNS Neurosci Ther 2016; 23:145-154. [PMID: 27976523 DOI: 10.1111/cns.12663] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 10/06/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022] Open
Abstract
AIMS Insular cortex (IC) is involved in processing the information of pain. The aim of this study was to investigate roles and mechanisms of P2X7 receptors (P2X7Rs) in IC in development of visceral hypersensitivity of adult rats with neonatal maternal deprivation (NMD). METHODS Visceral hypersensitivity was quantified by abdominal withdrawal reflex threshold to colorectal distension (CRD). Expression of P2X7Rs was determined by qPCR and Western blot. Synaptic transmission in IC was recorded by patch-clamp recording. RESULTS The expression of P2X7Rs and glutamatergic neurotransmission in IC was significantly increased in NMD rats when compared with age-matched controls. Application of BzATP (P2X7R agonist) enhanced the frequency of spontaneous excitatory postsynaptic currents (sEPSC) and miniature excitatory postsynaptic currents (mEPSC) in IC slices of control rats. Application of BBG (P2X7R antagonist) suppressed the frequencies of sEPSC and mEPSC in IC slices of NMD rats. Microinjection of BzATP into right IC significantly decreased CRD threshold in control rats while microinjection of BBG or A438079 into right IC greatly increased CRD threshold in NMD rats. CONCLUSION Data suggested that the enhanced activities of P2X7Rs in IC, likely through a presynaptic mechanism, contributed to visceral hypersensitivity of adult rats with NMD.
Collapse
Affiliation(s)
- Ping-An Zhang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Qi-Ya Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Lu Xue
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Hang Zheng
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jun Yan
- The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ying Xiao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China.,Chengdu Radio and TV University, Chengdu, China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Laboratory of Translational Pain Medicine, Institute of Neuroscience, Soochow University, Suzhou, China
| |
Collapse
|
|
41
|
Land WG, Agostinis P, Gasser S, Garg AD, Linkermann A. DAMP-Induced Allograft and Tumor Rejection: The Circle Is Closing. Am J Transplant 2016; 16:3322-3337. [PMID: 27529775 DOI: 10.1111/ajt.14012] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/28/2016] [Accepted: 07/31/2016] [Indexed: 01/25/2023]
Abstract
The pathophysiological importance of the immunogenicity of damage-associated molecular patterns (DAMPs) has been pinpointed by their identification as triggers of allograft rejection following release from dying cells, such as after ischemia-reperfusion injury. In cancers, however, this strong trigger of a specific immune response gives rise to the success of cancer immunotherapy. Here, we review the recently literature on the pathophysiological importance of DAMP release and discuss the implications of these processes for allograft rejection and cancer immunotherapy, revealing a striking mechanistic overlap. We conclude that these two fields share a common mechanistic basis of regulated necrosis and inflammation, the molecular characterization of which may be helpful for both oncologists and the transplant community.
Collapse
Affiliation(s)
- W G Land
- German Academy of Transplantation Medicine, Munich, Germany.,Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, Plateforme GENOMAX, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.,LabexTRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - P Agostinis
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - S Gasser
- Immunology Programme and Department of Microbiology and Immunology, Centre for Life Sciences, National University of Singapore, Singapore, Singapore
| | - A D Garg
- Cell Death Research and Therapy (CDRT) Lab, Department of Cellular and Molecular Medicine, KU Leuven, University of Leuven, Leuven, Belgium
| | - A Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.,Cluster of Excellence EXC306, Inflammation at Interfaces, Schleswig-Holstein, Germany.,Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany
| |
Collapse
|
|
42
|
Zeiser R, Robson SC, Vaikunthanathan T, Dworak M, Burnstock G. Unlocking the Potential of Purinergic Signaling in Transplantation. Am J Transplant 2016; 16:2781-2794. [PMID: 27005321 PMCID: PMC5472988 DOI: 10.1111/ajt.13801] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/11/2016] [Accepted: 03/19/2016] [Indexed: 01/25/2023]
Abstract
Purinergic signaling has been recognized as playing an important role in inflammation, angiogenesis, malignancy, diabetes and neural transmission. Activation of signaling pathways downstream from purinergic receptors may also be implicated in transplantation and related vascular injury. Following transplantation, the proinflammatory "danger signal" adenosine triphosphate (ATP) is released from damaged cells and promotes proliferation and activation of a variety of immune cells. Targeting purinergic signaling pathways may promote immunosuppression and ameliorate inflammation. Under pathophysiological conditions, nucleotide-scavenging ectonucleotidases CD39 and CD73 hydrolyze ATP, ultimately, to the anti-inflammatory mediator adenosine. Adenosine suppresses proinflammatory cytokine production and is associated with improved graft survival and decreased severity of graft-versus-host disease. Furthermore, purinergic signaling is involved both directly and indirectly in the mechanism of action of several existing immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. Targeting of purinergic receptor pathways, particularly in the setting of combination therapies, could become a valuable immunosuppressive strategy in transplantation. This review focuses on the role of the purinergic signaling pathway in transplantation and immunosuppression and explores possible future applications in clinical practice.
Collapse
Affiliation(s)
- R. Zeiser
- Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany
| | - S. C. Robson
- Department of Medicine, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA,Corresponding authors: Markus Dworak and Simon C. Robson, and
| | - T. Vaikunthanathan
- Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, King’s College London, Great Maze Pond, London, UK
| | - M. Dworak
- Novartis Pharma, Nuernberg, Germany,Institute of Movement and Neurosciences, German Sport University Cologne, Cologne, Germany,Corresponding authors: Markus Dworak and Simon C. Robson, and
| | - G. Burnstock
- Autonomic Neuroscience Centre, University College Medical School, London, UK,Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Australia
| |
Collapse
|
|
43
|
The impact of P2X7 receptor antagonist, brilliant blue G on graft-versus-host disease in mice after allogeneic hematopoietic stem cell transplantation. Cell Immunol 2016; 310:71-77. [PMID: 27544305 DOI: 10.1016/j.cellimm.2016.07.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 07/31/2016] [Accepted: 07/31/2016] [Indexed: 12/21/2022]
Abstract
The purpose of this study was to investigate the role of P2X7 on liver inflammation in mice after HSCT. Hematopoietic stem cells obtained from C57BL/6 mice were administrated into BALB/c mice to establish GVHD model. On day 7, 14, 21 and 28 after HSCT, mice received P2X7R antagonist brilliant blue G (BBG) or not were sacrificed for analysis of weight loss, liver inflammation, cytokine secretion, P2X7, NLRP3 expression as well as caspase-1 activation. Liver inflammation with neutrophils and macrophases infiltration as well as weight loss increase was present after HSCT, but improved after administration with high dose of BBG compared with lower dose. High dose of P2X7R inhibitor administration after HSCT previously reduced levels of IL-1β, IL-18, caspase-1, NLRP3 as well as P2X7, and the level of alanine transaminase (ALT) and the ratio of aspartate amino transferase (AST)/ALT compared with that receiving low dose of BBG. Meanwhile, P2X7R blockage also reduced infiltration of macrophages and neutrophils and levels of CXCL8 and CCL2 in peripheral blood as well as improved liver function. In conclusion, blockage of P2X7R by BBG exerts a protective effect on GVHD post HSCT and improves liver function suggesting that this receptor could be considered as an attractive target for treatment of GVHD.
Collapse
|
|
44
|
Abstract
Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.
Collapse
Affiliation(s)
- Caglar Cekic
- Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey
| | - Joel Linden
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
| |
Collapse
|
|
45
|
G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts. PLoS One 2016; 11:e0157245. [PMID: 27285580 PMCID: PMC4902232 DOI: 10.1371/journal.pone.0157245] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 05/26/2016] [Indexed: 12/16/2022] Open
Abstract
Background Allogeneic human islet transplantation is an effective therapy for the treatment of patients with Type 1 Diabetes (T1D). The low number of islet transplants performed worldwide and the different transplantation protocols used limit the identification of the most effective therapeutic options to improve the efficacy of this approach. Methods We present a retrospective analysis on the data collected from 44 patients with T1D who underwent islet transplantation at our institute between 2000 and 2007. Several variables were included: recipient demographics and immunological characteristics, donor and transplant characteristics, induction protocols, and additional medical treatment received. Immunosuppression was induced with anti-CD25 (Daclizumab), alone or in association with anti-tumor necrosis factor alpha (TNF-α) treatments (Etanercept or Infliximab), or with anti-CD52 (Alemtuzumab) in association with anti-TNF-α treatments (Etanercept or Infliximab). Subsets of patients were treated with Filgrastim for moderate/severe neutropenia and/or Exenatide for post prandial hyperglycemia. Results The analysis performed indicates a negative association between graft survival (c-peptide level ≥ 0.3 ng/ml) and islet infusion volume, with the caveat that, the progressive reduction of infusion volumes over the years has been paralleled by improved immunosuppressive protocols. A positive association is instead suggested between graft survival and administration of Exenatide and Filgrastim, alone or in combination. Conclusion This retrospective analysis may be of assistance to further improve long-term outcomes of protocols for transplant of islets and other organs.
Collapse
|
|
46
|
Abualhassan N, Sapozhnikov L, Pawlick RL, Kahana M, Pepper AR, Bruni A, Gala-Lopez B, Kin T, Mitrani E, Shapiro AMJ. Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation. PLoS One 2016; 11:e0156053. [PMID: 27227978 PMCID: PMC4881949 DOI: 10.1371/journal.pone.0156053] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 05/09/2016] [Indexed: 02/07/2023] Open
Abstract
There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.
Collapse
Affiliation(s)
| | - Lena Sapozhnikov
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rena L. Pawlick
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Meygal Kahana
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Andrew R. Pepper
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Antonio Bruni
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Boris Gala-Lopez
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Eduardo Mitrani
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - A. M. James Shapiro
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
47
|
Zhao R, Liang D, Sun D. Blockade of Extracellular ATP Effect by Oxidized ATP Effectively Mitigated Induced Mouse Experimental Autoimmune Uveitis (EAU). PLoS One 2016; 11:e0155953. [PMID: 27196432 PMCID: PMC4873015 DOI: 10.1371/journal.pone.0155953] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/07/2016] [Indexed: 12/20/2022] Open
Abstract
Various pathological conditions are accompanied by ATP release from the intracellular to the extracellular compartment. Extracellular ATP (eATP) functions as a signaling molecule by activating purinergic P2 purine receptors. The key P2 receptor involved in inflammation was identified as P2X7R. Recent studies have shown that P2X7R signaling is required to trigger the Th1/Th17 immune response, and oxidized ATP (oxATP) effectively blocks P2X7R activation. In this study we investigated the effect of oxATP on mouse experimental autoimmune uveitis (EAU). Our results demonstrated that induced EAU in B6 mice was almost completely abolished by the administration of small doses of oxATP, and the Th17 response, but not the Th1 response, was significantly weakened in the treated mice. Mechanistic studies showed that the therapeutic effects involve the functional change of a number of immune cells, including dendritic cells (DCs), T cells, and regulatory T cells. OxATP not only directly inhibits the T cell response; it also suppresses T cell activation by altering the function of DCs and Foxp3+ T cell. Our results demonstrated that inhibition of P2X7R activation effectively exempts excessive autoimmune inflammation, which may indicate a possible therapeutic use in the treatment of autoimmune diseases.
Collapse
Affiliation(s)
- Ronglan Zhao
- Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90033, United States of America
- Department of Medical Laboratory, Key Laboratory of Clinical Laboratory Diagnostics in the University of Shandong, Weifang Medical University, Weifang, 261053, Shandong, China
| | - Dongchun Liang
- Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90033, United States of America
| | - Deming Sun
- Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90033, United States of America
- * E-mail:
| |
Collapse
|
|
48
|
Geraghty NJ, Watson D, Adhikary SR, Sluyter R. P2X7 receptor in skin biology and diseases. World J Dermatol 2016; 5:72-83. [DOI: 10.5314/wjd.v5.i2.72] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/23/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
The P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer.
Collapse
|
|
49
|
Ma D, Duan W, Li Y, Wang Z, Li S, Gong N, Chen G, Chen Z, Wan C, Yang J. PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice. PLoS One 2016; 11:e0152087. [PMID: 26990974 PMCID: PMC4798758 DOI: 10.1371/journal.pone.0152087] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 03/08/2016] [Indexed: 12/21/2022] Open
Abstract
Background Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time. Methods Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients. Results PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity. Conclusions This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses.
Collapse
Affiliation(s)
- Dongxia Ma
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Wu Duan
- Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
| | - Yakun Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Zhimin Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Shanglin Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
| | - Chidan Wan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. China
- * E-mail: (JY); (CW)
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, Hubei Province, P. R. China
- * E-mail: (JY); (CW)
| |
Collapse
|
|
50
|
Shahbazov R, Kanak MA, Takita M, Kunnathodi F, Khan O, Borenstein N, Lawrence MC, Levy MF, Naziruddin B. Essential phospholipids prevent islet damage induced by proinflammatory cytokines and hypoxic conditions. Diabetes Metab Res Rev 2016; 32:268-77. [PMID: 26378630 DOI: 10.1002/dmrr.2714] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 07/10/2015] [Accepted: 08/03/2015] [Indexed: 01/19/2023]
Abstract
BACKGROUND The pancreatic islet damage that occurs through an inflammatory response and hypoxia after infusion is a major hurdle in islet transplantation. Because essential phospholipids (EPL) have been shown to exhibit anti-inflammatory properties in liver disease, we analysed their protective effect on islets in inflammatory or hypoxic conditions. METHODS We evaluated the viability of mouse and human islets cultured with cytokines or in hypoxic conditions for 48 h and measured cytokine expression in islets by quantitative polymerase chain reaction. We then employed an in vivo mouse assay, transplanting a marginal dose of human islets treated with or without EPL into the subcapsule of the kidney in diabetic nude mice and determining the cure rate. RESULTS The viability of mouse and human islets damaged by cytokines was significantly improved by supplementation of EPL in the culture (p = 0.003 and <0.001 for mouse and human islets respectively). EPL significantly inhibited intracellular expression of IL-1β and IL-6 in cytokine-damaged human islets (p < 0.001). The viability of human islets in hypoxic conditions was significantly better when treated with EPL (p < 0.001). In the in vivo mouse assay, the EPL-treated islet group had a higher cure rate than the untreated control, with marginal statistical significance (75 and 17% respectively, p = 0.07). CONCLUSIONS EPL could be a potent agent to protect islets from inflammatory and hypoxic conditions after isolation procedures. Further studies to clarify the effect of EPL in islet transplantation are warranted.
Collapse
Affiliation(s)
- Rauf Shahbazov
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | - Mazhar A Kanak
- The Institute of Biomedical Studies, Baylor University, Waco, TX, USA
| | - Morihito Takita
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | | | - Omar Khan
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | - Nofit Borenstein
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA
| | | | - Marlon F Levy
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| | - Bashoo Naziruddin
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA
| |
Collapse
|