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Yardeni T, Olali AZ, Chen HW, Wang L, Halton JA, Zenab A, Morrow R, Butic A, Murdock DG, Waymire KG, MacGregor GR, Boursi B, Beier UH, Hancock WW, Wallace DC. Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling. Proc Natl Acad Sci U S A 2025; 122:e2417252121. [PMID: 39752523 PMCID: PMC11725793 DOI: 10.1073/pnas.2417252121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 11/25/2024] [Indexed: 01/15/2025] Open
Abstract
Mitochondrial DNA (mtDNA) is highly polymorphic, and host mtDNA variation has been associated with altered cancer severity. To determine the basis of this mtDNA-cancer association, we analyzed conplastic mice with the C57BL/6J (B6) nucleus but two naturally occurring mtDNA lineages, mtDNAB6 and mtDNANZB, where mtDNANZB mitochondria generate more oxidative phosphorylation (OXPHOS)-derived reactive oxygen species (mROS). In a cardiac transplant model, mtDNAB6 Foxp3+ T regulatory (Treg) cells supported long-term allograft survival, whereas mtDNANZB Treg cells failed to suppress host T effector (Teff) cells, leading to acute rejection. When challenged with melanoma or colon cancer cells, the mtDNANZB mice exhibited strikingly impaired tumor growth while mtDNAB6 mice showed Treg-dependent inhibition of Teff cells and allowed rapid tumor growth. Transcriptional analysis showed that activation of mtDNANZB Teff cells increased mitochondrial gene expression while activation of mtDNANZB Treg cells impaired mitochondrial gene expression and resulted in mtDNANZB Treg cell exhaustion. Induction of the mitochondrially targeted catalytic antioxidant, mCAT, in hematopoietic cells normalized mtDNANZB Treg function in both transplant and tumor models, indicating a key role for mROS in promoting Treg dysfunction. Anti-PD-L1 therapy did not modulate these effects, indicating that modulation of host mitochondrial function provides an independent approach for enhancing tumor cell destruction.
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Affiliation(s)
- Tal Yardeni
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Bert Strassburger Metabolic Center for Preventive Medicine, Sheba Medical Center, Tel Hashomer5262000, Israel
| | - Arnold Z. Olali
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Hsiao-Wen Chen
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Liqing Wang
- Division of Transplant Immunology, Children’s Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Jeffrey A. Halton
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Angi Zenab
- Bert Strassburger Metabolic Center for Preventive Medicine, Sheba Medical Center, Tel Hashomer5262000, Israel
| | - Ryan Morrow
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Arrienne Butic
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
| | - Deborah G. Murdock
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Katrina G. Waymire
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697-2300
| | - Grant R. MacGregor
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697-2300
| | - Ben Boursi
- Division of Oncology, Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Tel Aviv5262000, Israel
- Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Ulf H. Beier
- Immunology, Johnson & Johnson Innovative Medicine, Spring House, PA19477
| | - Wayne W. Hancock
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Division of Transplant Immunology, Children’s Hospital of Philadelphia and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA19104
| | - Douglas C. Wallace
- Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA19104
- Division of Human Genetics, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104
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Hu L, Liu W, Yin L, Yi X, Zou Y, Sheng X. Analysis of factors influencing the recurrence of diabetic foot ulcers. Skin Res Technol 2024; 30:e13826. [PMID: 38965804 PMCID: PMC11224123 DOI: 10.1111/srt.13826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/03/2024] [Accepted: 06/08/2024] [Indexed: 07/06/2024]
Abstract
OBJECTIVE The aim of this study is to investigate the factors influencing the recurrence of diabetic foot ulcers (DFU) and provide guidance for reducing the recurrence rate. METHODS A total of 211 patients diagnosed with DFU who were hospitalized and discharged from the hospital from October 2015 to January 2020 were included as the study cohort. Participants were divided into two groups according to whether the foot ulcer recurred during the 2-year follow-up period: a recurrence group (n = 84) and a non-recurrence group (n = 127). The following data were collected and analyzed for the two groups of patients: general information, foot information, laboratory indicators, diabetes comorbidities, and complications. RESULTS (1) The overall recurrence rate of diabetic foot ulcers (DFU) within 2 years was 39.8%, indicating a high recurrence rate. (2) Significant differences were observed between the two patient groups in terms of BMI, HbA1c, TBIL, CRP, financial situation, foot deformity, first ulcer on the sole of the foot, previous amputation history, Wagner grade of the first ulcer, osteomyelitis, DFU duration (>60 days), lower limb vascular reconstruction, peripheral arterial disease (PAD), and diabetic peripheral neuropathy (DPN) (t = 2.455; Z = -1.988, -3.731, -3.618; χ2 = 7.88, 5.004, 3.906, 17.178, 16.237, 5.007, 24.642, 4.782, 29.334, 10.253). No significant differences were found for the other indicators. (3) Logistic regression analysis revealed that TBIL (OR = 0.886, p = 0.036) was a protective factor against ulcer recurrence. In contrast, PAD, previous amputation history, DPN, and the first ulcer on the sole of the foot (OR = 3.987, 6.758, 4.681, 2.405; p < 0.05 or p < 0.01) were identified as risk factors for ulcer recurrence. CONCLUSION Early screening and preventive education targeting high-risk factors such as DPN, PAD and the initial ulcer location on the sole of the foot are essential to mitigate the high long-term recurrence rate of DFU. Furthermore, the protective role of TBIL in preventing ulcer recurrence underscores the importance of monitoring bilirubin levels as part of a comprehensive management strategy for DFU patients.
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Affiliation(s)
- Ling Hu
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
| | - Wenjuan Liu
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
| | - Liqin Yin
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
| | - Xiaoling Yi
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
| | - Yi Zou
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
| | - Xia Sheng
- Department of EndocrinologyThe Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang)NanchangJiangxiChina
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Tseng HT, Lin YW, Huang CY, Shih CM, Tsai YT, Liu CW, Tsai CS, Lin FY. Animal Models for Heart Transplantation Focusing on the Pathological Conditions. Biomedicines 2023; 11:biomedicines11051414. [PMID: 37239085 DOI: 10.3390/biomedicines11051414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Cardiac transplant recipients face many complications due to transplant rejection. Scientists must conduct animal experiments to study disease onset mechanisms and develop countermeasures. Therefore, many animal models have been developed for research topics including immunopathology of graft rejection, immunosuppressive therapies, anastomotic techniques, and graft preservation techniques. Small experimental animals include rodents, rabbits, and guinea pigs. They have a high metabolic rate, high reproductive rate, small size for easy handling, and low cost. Additionally, they have genetically modified strains for pathological mechanisms research; however, there is a lacuna, as these research results rarely translate directly to clinical applications. Large animals, including canines, pigs, and non-human primates, have anatomical structures and physiological states that are similar to those of humans; therefore, they are often used to validate the results obtained from small animal studies and directly speculate on the feasibility of applying these results in clinical practice. Before 2023, PubMed Central® at the United States National Institute of Health's National Library of Medicine was used for literature searches on the animal models for heart transplantation focusing on the pathological conditions. Unpublished reports and abstracts from conferences were excluded from this review article. We discussed the applications of small- and large-animal models in heart transplantation-related studies. This review article aimed to provide researchers with a complete understanding of animal models for heart transplantation by focusing on the pathological conditions created by each model.
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Affiliation(s)
- Horng-Ta Tseng
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Wen Lin
- Institute of Oral Biology, National Yang Ming Chiao Tung University (Yangming Campus), Taipei 112304, Taiwan
| | - Chun-Yao Huang
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Ming Shih
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
| | - Chen-Wei Liu
- Department of Basic Medical Science, College of Medicine, University of Arizona, Phoenix, AZ 85721, USA
| | - Chien-Sung Tsai
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Feng-Yen Lin
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Billah M, Naz A, Noor R, Bhindi R, Khachigian LM. Early Growth Response-1: Friend or Foe in the Heart? Heart Lung Circ 2023; 32:e23-e35. [PMID: 37024319 DOI: 10.1016/j.hlc.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 04/07/2023]
Abstract
Cardiovascular disease is a major cause of mortality and morbidity worldwide. Early growth response-1 (Egr-1) plays a critical regulatory role in a range of experimental models of cardiovascular diseases. Egr-1 is an immediate-early gene and is upregulated by various stimuli including shear stress, oxygen deprivation, oxidative stress and nutrient deprivation. However, recent research suggests a new, underexplored cardioprotective side of Egr-1. The main purpose of this review is to explore and summarise the dual nature of Egr-1 in cardiovascular pathobiology.
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Affiliation(s)
- Muntasir Billah
- Department of Cardiology, Kolling Institute of Medical Research, Northern Sydney Local Health District, Sydney, NSW, Australia; Sydney Medical School Northern, The University of Sydney, Sydney, NSW, Australia.
| | - Adiba Naz
- Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
| | - Rashed Noor
- School of Environmental and Life Sciences, Independent University Bangladesh, Dhaka, Bangladesh
| | - Ravinay Bhindi
- Department of Cardiology, Kolling Institute of Medical Research, Northern Sydney Local Health District, Sydney, NSW, Australia; Sydney Medical School Northern, The University of Sydney, Sydney, NSW, Australia
| | - Levon M Khachigian
- Vascular Biology and Translational Research, School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
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Cardiovascular Risk after Kidney Transplantation: Causes and Current Approaches to a Relevant Burden. J Pers Med 2022; 12:jpm12081200. [PMID: 35893294 PMCID: PMC9329988 DOI: 10.3390/jpm12081200] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Cardiovascular disease is a frequent complication after kidney transplantation and represents the leading cause of mortality in this population. Material and Methods. We searched for the relevant articles in the National Institutes of Health library of medicine, transplant, cardiologic and nephrological journals. Results. The pathogenesis of cardiovascular disease in kidney transplant is multifactorial. Apart from non-modifiable risk factors, such as age, gender, genetic predisposition and ethnicity, several traditional and non-traditional modifiable risk factors contribute to its development. Traditional factors, such as diabetes, hypertension and dyslipidemia, may be present before and may worsen after transplantation. Immunosuppressants and impaired graft function may strongly influence the exacerbation of these comorbidities. However, in the last years, several studies showed that many other cardiovascular risk factors may be involved in kidney transplantation, including hyperuricemia, inflammation, low klotho and elevated Fibroblast Growth Factor 23 levels, deficient levels of vitamin D, vascular calcifications, anemia and poor physical activity and quality of life. Conclusions. The timely and effective treatment of time-honored and recently discovered modifiable risk factors represent the basis of the prevention of cardiovascular complications in kidney transplantation. Reduction of cardiovascular risk can improve the life expectancy, the quality of life and the allograft function and survival.
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Ponticelli C, Campise MR. The inflammatory state is a risk factor for cardiovascular disease and graft fibrosis in kidney transplantation. Kidney Int 2021; 100:536-545. [PMID: 33932457 DOI: 10.1016/j.kint.2021.04.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023]
Abstract
Several factors, such as donor brain death, ischemia-reperfusion injury, rejection, infection, and chronic allograft dysfunction, may induce an inflammatory state in kidney transplantation. Furthermore, inflammatory cells, cytokines, growth factors, complement and coagulation cascade create an unbalanced interaction with innate and adaptive immunity, which are both heavily involved in atherogenesis. The crosstalk between inflammation and thrombosis may lead to a prothrombotic state and impaired fibrinolysis in kidney transplant recipients increasing the risk of cardiovascular disease. Inflammation is also associated with elevated levels of fibroblast growth factor 23 and low levels of Klotho, which contribute to major adverse cardiovascular events. Hyperuricemia, glucose intolerance, arterial hypertension, dyslipidemia, and physical inactivity may create a condition called metaflammation that concurs in atherogenesis. Another major consequence of the inflammatory state is the development of chronic hypoxia that through the mediation of interleukins 1 and 6, angiotensin II, and transforming growth factor beta can result in excessive accumulation of extracellular matrix, which can disrupt and replace functional parenchyma, leading to interstitial fibrosis and chronic allograft dysfunction. Lifestyle and regular physical activity may reduce inflammation. Several drugs have been proposed to control the graft inflammatory state, including low-dose aspirin, statins, renin-angiotensin inhibitors, xanthine-oxidase inhibitors, vitamin D supplements, and interleukin-6 blockade. However, no prospective controlled trial with these measures has been conducted in kidney transplantation.
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Affiliation(s)
- Claudio Ponticelli
- Division of Nephrology, Ospedale Maggiore Policlinico, Milano, Italy (retired).
| | - Maria Rosaria Campise
- Division of Nephrology and Dialysis, Ca' Granda Foundation, Scientific Institute Ospedale Maggiore Policlinico di Milano, Milano, Italy
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Grunenwald A, Roumenina LT, Frimat M. Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases. Int J Mol Sci 2021; 22:2009. [PMID: 33670516 PMCID: PMC7923026 DOI: 10.3390/ijms22042009] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022] Open
Abstract
The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney's filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1's role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.
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Affiliation(s)
- Anne Grunenwald
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France; (A.G.); (L.T.R.)
| | - Lubka T. Roumenina
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France; (A.G.); (L.T.R.)
| | - Marie Frimat
- U1167-RID-AGE, Institut Pasteur de Lille, Inserm, Univ. Lille, F-59000 Lille, France
- Nephrology Department, CHU Lille, Univ. Lille, F-59000 Lille, France
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Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease. Antioxidants (Basel) 2020; 9:antiox9090829. [PMID: 32899732 PMCID: PMC7554957 DOI: 10.3390/antiox9090829] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase-1 (HO-1) catalyzes the degradation of heme into carbon monoxide (CO), iron, and biliverdin, which is rapidly metabolized to bilirubin. The activation of vascular smooth muscle cells (SMCs) plays a critical role in mediating the aberrant arterial response to injury and a number of vascular diseases. Pharmacological induction or gene transfer of HO-1 improves arterial remodeling in animal models of post-angioplasty restenosis, vascular access failure, atherosclerosis, transplant arteriosclerosis, vein grafting, and pulmonary arterial hypertension, whereas genetic loss of HO-1 exacerbates the remodeling response. The vasoprotection evoked by HO-1 is largely ascribed to the generation of CO and/or the bile pigments, biliverdin and bilirubin, which exert potent antioxidant and anti-inflammatory effects. In addition, these molecules inhibit vascular SMC proliferation, migration, apoptosis, and phenotypic switching. Several therapeutic strategies are currently being pursued that may allow for the targeting of HO-1 in arterial remodeling in various pathologies, including the use of gene delivery approaches, the development of novel inducers of the enzyme, and the administration of unique formulations of CO and bilirubin.
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Wang L, Wang Z, Han R, Samanta A, Ge G, Levin LS, Levine MH, Hancock WW. Donor bone-marrow CXCR4+ Foxp3+ T-regulatory cells are essential for costimulation blockade-induced long-term survival of murine limb transplants. Sci Rep 2020; 10:9292. [PMID: 32518311 PMCID: PMC7283338 DOI: 10.1038/s41598-020-66139-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/30/2020] [Indexed: 12/12/2022] Open
Abstract
Vascularized composite allotransplantation (VCA) allows tissue replacement after devastating loss but is currently limited in application and may be more widely performed if maintenance immunosuppression was not essential for graft acceptance. We tested whether peri-transplant costimulation blockade could prolong VCA survival and required donor bone-marrow cells, given that bone-marrow might promote graft immunogenicity or graft-versus-host disease. Peritransplant CD154 mAb/rapamycin (RPM) induced long-term orthotopic hindlimb VCA survival (BALB/c->C57BL/6), as did CTLA4Ig/RPM. Surprisingly, success of either protocol required a bone-marrow-associated, radiation-sensitive cell population, since long-bone removal or pre-transplant donor irradiation prevented long-term engraftment. Rejection also occurred if Rag1−/− donors were used, or if donors were treated with a CXCR4 inhibitor to mobilize donor BM cells pre-transplant. Donor bone-marrow contained a large population of Foxp3+ T-regulatory (Treg) cells, and donor Foxp3+ Treg depletion, by diphtheria toxin administration to DEREG donor mice whose Foxp3+ Treg cells expressed diphtheria toxin receptor, restored rejection with either protocol. Rejection also occurred if CXCR4 was deleted from donor Tregs pre-transplant. Hence, long-term VCA survival is possible across a full MHC disparity using peritransplant costimulation blockade-based approaches, but unexpectedly, the efficacy of costimulation blockade requires the presence of a radiation-sensitive, CXCR4+ Foxp3+ Treg population resident within donor BM.
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Affiliation(s)
- Liqing Wang
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Zhonglin Wang
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rongxiang Han
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Arabinda Samanta
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.,Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Guanghui Ge
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - L Scott Levin
- Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Surgery, Division of Plastic Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Matthew H Levine
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Wayne W Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA.
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10
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Corona D, Ekser B, Gioco R, Caruso M, Schipa C, Veroux P, Giaquinta A, Granata A, Veroux M. Heme-Oxygenase and Kidney Transplantation: A Potential for Target Therapy? Biomolecules 2020; 10:E840. [PMID: 32486245 PMCID: PMC7355572 DOI: 10.3390/biom10060840] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022] Open
Abstract
Kidney transplantation is a well-established therapy for patients with end-stage renal disease. While a significant improvement of short-term results has been achieved in the short-term, similar results were not reported in the long-term. Heme-oxygenase (HO) is the rate-limiting enzyme in heme catabolism, converting heme to iron, carbon monoxide, and biliverdin. Heme-oxygenase overexpression may be observed in all phases of transplant processes, including brain death, recipient management, and acute and chronic rejection. HO induction has been proved to provide a significant reduction of inflammatory response and a reduction of ischemia and reperfusion injury in organ transplantation, as well as providing a reduction of incidence of acute rejection. In this review, we will summarize data on HO and kidney transplantation, suggesting possible clinical applications in the near future to improve the long-term outcomes.
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Affiliation(s)
- Daniela Corona
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (D.C.); (M.C.)
- Organ Transplant Unit, University Hospital of Catania, 95123 Catania, Italy; (P.V.); (A.G.)
| | - Burcin Ekser
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46077, USA;
| | - Rossella Gioco
- General Surgery Unit, University Hospital of Catania, 95123 Catania, Italy; (R.G.); (C.S.)
| | - Massimo Caruso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (D.C.); (M.C.)
| | - Chiara Schipa
- General Surgery Unit, University Hospital of Catania, 95123 Catania, Italy; (R.G.); (C.S.)
| | - Pierfrancesco Veroux
- Organ Transplant Unit, University Hospital of Catania, 95123 Catania, Italy; (P.V.); (A.G.)
| | - Alessia Giaquinta
- Organ Transplant Unit, University Hospital of Catania, 95123 Catania, Italy; (P.V.); (A.G.)
| | | | - Massimiliano Veroux
- Organ Transplant Unit, University Hospital of Catania, 95123 Catania, Italy; (P.V.); (A.G.)
- General Surgery Unit, University Hospital of Catania, 95123 Catania, Italy; (R.G.); (C.S.)
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11
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Ochando J, Fayad ZA, Madsen JC, Netea MG, Mulder WJM. Trained immunity in organ transplantation. Am J Transplant 2020; 20:10-18. [PMID: 31561273 PMCID: PMC6940521 DOI: 10.1111/ajt.15620] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 09/11/2019] [Accepted: 09/15/2019] [Indexed: 01/25/2023]
Abstract
Consistent induction of donor-specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen-presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long-term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro-inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.
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Affiliation(s)
- Jordi Ochando
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew York,Transplant Immunology UnitNational Center of MicrobiologyInstituto de Salud Carlos IIIMadridSpain
| | - Zahi A. Fayad
- Department of RadiologyTranslational and Molecular Imaging InstituteIcahn School of Medicine at Mount SinaiNew YorkNew York
| | - Joren C. Madsen
- Center for Transplantation Sciences and Division of Cardiac SurgeryDepartment of SurgeryMassachusetts General HospitalBostonMassachusetts
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious DiseasesRadboud University Medical CenterNijmegenThe Netherlands,Department for Genomics & ImmunoregulationLife and Medical Sciences Institute (LIMES)University of BonnBonnGermany
| | - Willem J. M. Mulder
- Department of Oncological SciencesIcahn School of Medicine at Mount SinaiNew YorkNew York,Department of RadiologyTranslational and Molecular Imaging InstituteIcahn School of Medicine at Mount SinaiNew YorkNew York,Laboratory of Chemical BiologyDepartment of Biomedical EngineeringInstitute for Complex Molecular SystemsEindhoven University of TechnologyEindhovenThe Netherlands
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12
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Pogu J, Tzima S, Kollias G, Anegon I, Blancou P, Simon T. Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice. Int J Mol Sci 2019; 20:ijms20071676. [PMID: 30987262 PMCID: PMC6480274 DOI: 10.3390/ijms20071676] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 11/16/2022] Open
Abstract
Antigen-presenting cells (APCs) including dendritic cells (DCs) play a critical role in the development of autoimmune diseases by presenting self-antigen to T-cells. Different signals modulate the ability of APCs to activate or tolerize autoreactive T-cells. Since the expression of heme oxygenase-1 (HO-1) by APCs has been associated with the tolerization of autoreactive T-cells, we hypothesized that HO-1 expression might be altered in APCs from autoimmune-prone non-obese diabetic (NOD) mice. We found that, compared to control mice, NOD mice exhibited a lower percentage of HO-1-expressing cells among the splenic DCs, suggesting an impairment of their tolerogenic functions. To investigate whether restored expression of HO-1 in APCs could alter the development of diabetes in NOD mice, we generated a transgenic mouse strain in which HO-1 expression can be specifically induced in DCs using a tetracycline-controlled transcriptional activation system. Mice in which HO-1 expression was induced in DCs exhibited a lower Type 1 Diabetes (T1D) incidence and a reduced insulitis compared to non-induced mice. Upregulation of HO-1 in DCs also prevented further increase of glycemia in recently diabetic NOD mice. Altogether, our data demonstrated the potential of induction of HO-1 expression in DCs as a preventative treatment, and potential as a curative approach for T1D.
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Affiliation(s)
- Julien Pogu
- Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé Et de la Recherche Médicale (INSERM), Université de Nantes, 44000 Nantes, France.
| | - Sotiria Tzima
- Institute of Immunology, Biomedical Sciences Research Centre "Alexander Fleming", Vari, 210 Attica, Greece.
| | - Georges Kollias
- Institute of Immunology, Biomedical Sciences Research Centre "Alexander Fleming", Vari, 210 Attica, Greece.
| | - Ignacio Anegon
- Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé Et de la Recherche Médicale (INSERM), Université de Nantes, 44000 Nantes, France.
| | - Philippe Blancou
- Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé Et de la Recherche Médicale (INSERM), Université de Nantes, 44000 Nantes, France.
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France.
| | - Thomas Simon
- Centre de Recherche en Transplantation et Immunologie, Institut National de la Santé Et de la Recherche Médicale (INSERM), Université de Nantes, 44000 Nantes, France.
- Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France.
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13
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Chhabra M, Alsughayyir J, Qureshi MS, Mallik M, Ali JM, Gamper I, Moseley EL, Peacock S, Kosmoliaptsis V, Goddard MJ, Linterman MA, Motallebzadeh R, Pettigrew GJ. Germinal Center Alloantibody Responses Mediate Progression of Chronic Allograft Injury. Front Immunol 2019; 9:3038. [PMID: 30728823 PMCID: PMC6351502 DOI: 10.3389/fimmu.2018.03038] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 12/07/2018] [Indexed: 02/02/2023] Open
Abstract
Different profiles of alloantibody responses are observed in the clinic, with those that persist, often despite targeted treatment, associated with poorer long-term transplant outcomes. Although such responses would suggest an underlying germinal center (GC) response, the relationship to cellular events within the allospecific B cell population is unclear. Here we examine the contribution of germinal center (GC) humoral alloimmunity to chronic antibody mediated rejection (AMR). A murine model of chronic AMR was developed in which T cell deficient (Tcrbd-/-) C57BL/6 recipients were challenged with MHC-mismatched BALB/c heart allografts and T cell help provided by reconstituting with 103 "TCR75" CD4 T cells that recognize self-restricted allopeptide derived from the H-2Kd MHC class I alloantigen. Reconstituted recipients developed Ig-switched anti-Kd alloantibody responses that were slow to develop, but long-lived, with confocal immunofluorescence and flow cytometric characterization of responding H-2Kd-allospecific B cells confirming persistent splenic GC activity. This was associated with T follicular helper (TFH) cell differentiation of the transferred TCR75 CD4 T cells. Heart grafts developed progressive allograft vasculopathy, and were rejected chronically (MST 50 days), with explanted allografts displaying features of humoral vascular rejection. Critically, late alloantibody responses were abolished, and heart grafts survived indefinitely, in recipients reconstituted with Sh2d1a-/- TCR75 CD4 T cells that were genetically incapable of providing TFH cell function. The GC response was associated with affinity maturation of the anti-Kd alloantibody response, and its contribution to progression of allograft vasculopathy related principally to secretion of alloantibody, rather than to enhanced alloreactive T cell priming, because grafts survived long-term when B cells could present alloantigen, but not secrete alloantibody. Similarly, sera sampled at late time points from chronically-rejecting recipients induced more vigorous donor endothelial responses in vitro than sera sampled earlier after transplantation. In summary, our results suggest that chronic AMR and progression of allograft vasculopathy is dependent upon allospecific GC activity, with critical help provided by TFH cells. Clinical strategies that target the TFH cell subset may hold therapeutic potential. This work is composed of two parts, of which this is Part II. Please read also Part I: Alsughayyir et al., 2019.
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Affiliation(s)
- Manu Chhabra
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Jawaher Alsughayyir
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - M. Saeed Qureshi
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Mekhola Mallik
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Jason M. Ali
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Ivonne Gamper
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Ellen L. Moseley
- Department of Pathology, Papworth Hospital, Papworth Everard, United Kingdom
| | - Sarah Peacock
- Histocompatibility and Immunogenetics Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Martin J. Goddard
- Department of Pathology, Papworth Hospital, Papworth Everard, United Kingdom
| | - Michelle A. Linterman
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Reza Motallebzadeh
- Division of Surgery and Interventional Science, University College London, London, United Kingdom
- Centre for Transplantation, Department of Renal Medicine, University College London, London, United Kingdom
- Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Gavin J. Pettigrew
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
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14
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Tatapudi VS, Min ES, Gelb BE, Dagher NN, Montgomery RA, Lonze BE. Repeat A2 Into B Kidney Transplantation After Failed Prior A2 Into B Transplant: A Case Report. Transplant Proc 2018; 50:3913-3916. [PMID: 30471832 DOI: 10.1016/j.transproceed.2018.06.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 06/27/2018] [Indexed: 12/19/2022]
Abstract
Kidneys from donors with blood type A2 can be successfully transplanted into blood type B and O recipients without the need for desensitization if the recipient's starting anti-A hemagglutinin titer is within an acceptable range. National kidney allocation policy now offers priority for eligible B recipients to receive A2 or A2B deceased donor kidneys, and therefore, the frequency with which A2 or A2B to B transplants will occur is expected to increase. The precise mechanisms by which antibody-mediated rejection is averted in these cases despite the presence of both circulating anti-A antibody and expression of the A2 antigen on the graft endothelium are not known. Whether this process mirrors proposed mechanisms of accommodation, which can occur in recipients of ABO incompatible transplants, is also not known. Repeated exposure to mismatched antigens after retransplantation could elicit memory responses resulting in antibody rebound and accelerated antibody-mediated rejection. Whether this would occur in the setting of repeated A2 donor exposure was uncertain. Here we report the case of a patient with history of a prior A2 to B transplant which failed owing to nonimmunologic reasons; the patient successfully underwent a repeat A2 to B transplant. Neither rebound in anti-A2 antibody nor clinical evidence of antibody-mediated rejection were observed after the transplant. Current kidney allocation will likely enable more such transplants in the future, and this may provide a unique patient population in whom the molecular mechanisms of incompatible graft accommodation may be investigated.
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Affiliation(s)
- V S Tatapudi
- Transplant Institute, New York University Langone Health, New York, NY
| | - E S Min
- Transplant Institute, New York University Langone Health, New York, NY
| | - B E Gelb
- Transplant Institute, New York University Langone Health, New York, NY
| | - N N Dagher
- Transplant Institute, New York University Langone Health, New York, NY
| | - R A Montgomery
- Transplant Institute, New York University Langone Health, New York, NY
| | - B E Lonze
- Transplant Institute, New York University Langone Health, New York, NY.
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15
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Curcumin Inhibits Acute Vascular Inflammation through the Activation of Heme Oxygenase-1. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3295807. [PMID: 30327711 PMCID: PMC6171216 DOI: 10.1155/2018/3295807] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/03/2018] [Accepted: 07/19/2018] [Indexed: 11/24/2022]
Abstract
Curcumin has several therapeutic properties such as anti-inflammatory effect. Heme oxygenase-1 (HO-1) has been showed to have cytoprotective effects in some pathological conditions. However, the role of HO-1 in anti-inflammatory effect of curcumin is unknown. In this study, we investigate whether the anti-inflammatory effect of curcumin in vascular may be involved in the activation of HO-1. New Zealand white rabbits were fed regular control diet or control diet added with 0.3% curcumin (wt/wt) for four weeks. Acute vascular inflammation of rabbits was induced by putting a collar on the left common carotid artery for 24 hours. HO-1 inhibitor and siRNA were used to investigate the role of HO-1 in the anti-inflammatory effect of curcumin in collared vascular. We also explored the mechanism of curcumin-induced activation of HO-1 in vitro. The serum bilirubin and vascular, liver, and spleen HO-1 mRNA levels were significantly increased in curcumin-treated rabbits. The vascular inflammation was significantly decreased in the curcumin-treated animals compared with the control. Treatment of the rabbits with an inhibitor of HO or HO-1 siRNA to knock down the carotid artery HO-1 abolished the ability of curcumin to inhibit vascular inflammation. Treatment of cultured human artery endothelial cells with curcumin induced the HO-1 expression through the activation of nuclear factor-E2-related factor 2 (Nrf2) and an antioxidant responsive element via the p38 MAPK signalling pathway. In conclusion, curcumin inhibits vascular inflammation in vivo and in vitro through the activation of HO-1.
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16
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Kucukal E, Ilich A, Key NS, Little JA, Gurkan UA. Red Blood Cell Adhesion to Heme-Activated Endothelial Cells Reflects Clinical Phenotype in Sickle Cell Disease. Am J Hematol 2018; 93:10.1002/ajh.25159. [PMID: 29905377 PMCID: PMC6295270 DOI: 10.1002/ajh.25159] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 12/19/2022]
Abstract
In sickle cell disease (SCD), 'disease severity' associates with increased RBC adhesion to quiescent endothelium, but the impact on activated endothelium is not known. Increased concentrations of free heme result from intravascular hemolysis in SCD. Heme is essential for aerobic metabolism, and plays an important role in numerous biological processes. Excess free heme induces reactive oxygen species generation and endothelial activation, which are associated with cardiovascular disorders including atherosclerosis, hypertension, and thrombosis. Here, we utilized an endothelialized microfluidic platform (Endothelium-on-a-chip) to assess adhesion of sickle hemoglobin-containing red blood cells (HbS RBCs), from adults with homozygous SCD, to heme-activated human endothelial cells (EC) in vitro. Confluent EC monolayers in microchannels were treated with pathophysiologically relevant levels of heme in order to simulate the highly hemolytic intravascular milieu seen in SCD. RBC adhesion to heme-activated ECs varied from subject to subject, and was associated with plasma markers of hemolysis (LDH) and reticulocytosis, thereby linking those RBCs that are most likely to adhere with those that are most likely to hemolyze. These results re-emphasize the critical contribution made by heterogeneous adhesive HbS RBCs to the pathophysiology of SCD. We found that adhesion of HbS RBCs to heme-activated ECs varied amongst individuals in the study population, and associated with biomarkers of hemolysis and inflammation, age, and a recent history of transfusion. Importantly, the microfluidic approach described herein holds promise as a clinically feasible Endothelium-on-a-chip platform with which to study complex heterocellular adhesive interactions in SCD. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Erdem Kucukal
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Anton Ilich
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Nigel S. Key
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Jane A. Little
- Division of Hematology/Oncology, Case Western Reserve University, University Hospitals Seidman Cancer Center, Cleveland, OH, USA
| | - Umut A. Gurkan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
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17
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Heinemann FM, Jindra PT, Bockmeyer CL, Zeuschner P, Wittig J, Höflich H, Eßer M, Abbas M, Dieplinger G, Stolle K, Vester U, Hoyer PF, Immenschuh S, Heinold A, Horn PA, Li W, Eisenberger U, Becker JU. Glomerulocapillary miRNA response to HLA-class I antibody in vitro and in vivo. Sci Rep 2017; 7:14554. [PMID: 29109529 PMCID: PMC5673998 DOI: 10.1038/s41598-017-14674-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 10/16/2017] [Indexed: 01/12/2023] Open
Abstract
Changes in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes. A better understanding could lead to novel diagnostic tools and reveal novel therapeutic targets. We explored deregulated miRNAs in an glomeruloendothelial in vitro model of ABMR due to class I human leukocyte antigen (HLA) with and without complement activation. We studied a set of 16 promising candidate miRNAs in microdissected glomeruli a confirmation set of 20 human transplant biopsies (DSA+) compared to 10 matched controls without evidence for ABMR. Twelve out of these 16 glomerulocapillary miRNAs could successfully be confirmed as dysregulated in vivo with 10 upregulated (let-7c-5p, miR-28-3p, miR-30d-5p, miR-99b-5p, miR-125a-5p, miR-195-5p, miR-374b-3p, miR-484, miR-501-3p, miR-520e) and 2 downregulated (miR29b-3p, miR-885-5p) in DSA+ vs. CONTROLS A random forest analysis based on glomerular miRNAs identified 18/20 DSA+ and 8/10 controls correctly. This glomerulocapillary miRNA signature associated with HLA class I-DSA could improve our understanding of ABMR and be useful for diagnostic or therapeutic purposes.
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Affiliation(s)
- Falko M Heinemann
- Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Peter T Jindra
- Immune Evaluation Laboratory, Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Clemens L Bockmeyer
- Institute of Pathology, Department of Nephropathology, University Hospital Erlangen-Nürnberg, Erlangen, Germany
| | - Philip Zeuschner
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Juliane Wittig
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Heike Höflich
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Marc Eßer
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | | | - Georg Dieplinger
- Department of General, Visceral and Cancer Surgery, Transplant Center Cologne, University of Cologne, Cologne, Germany
| | - Katharina Stolle
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Udo Vester
- Children's Hospital, Pediatrics II, University of Duisburg-Essen, Essen, Germany
| | - Peter F Hoyer
- Children's Hospital, Pediatrics II, University of Duisburg-Essen, Essen, Germany
| | - Stephan Immenschuh
- Institute of Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Andreas Heinold
- Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Peter A Horn
- Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Wentian Li
- Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Ute Eisenberger
- Clinic for Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jan U Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
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18
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Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function. Sci Rep 2017; 7:8626. [PMID: 28819166 PMCID: PMC5561267 DOI: 10.1038/s41598-017-09211-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 07/21/2017] [Indexed: 12/13/2022] Open
Abstract
Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
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19
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Otterbein LE, Foresti R, Motterlini R. Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival. Circ Res 2017; 118:1940-1959. [PMID: 27283533 DOI: 10.1161/circresaha.116.306588] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/02/2016] [Indexed: 12/22/2022]
Abstract
Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.
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Affiliation(s)
- Leo E Otterbein
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Roberta Foresti
- Inserm, U955, Equipe 12, Créteil, 94000, France.,University Paris Est, Faculty of Medicine, Créteil, 94000, France
| | - Roberto Motterlini
- Inserm, U955, Equipe 12, Créteil, 94000, France.,University Paris Est, Faculty of Medicine, Créteil, 94000, France
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20
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Lee CH, Hsieh MJ, Chang SH, Chiang CL, Fan CL, Liu SJ, Chen WJ, Wang CJ, Hsu MY, Hung KC, Chou CC, Chang PC. Biodegradable Cable-Tie Rapamycin-eluting Stents. Sci Rep 2017; 7:111. [PMID: 28273914 PMCID: PMC5427919 DOI: 10.1038/s41598-017-00131-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 02/08/2017] [Indexed: 12/03/2022] Open
Abstract
"Cable-tie" type biodegradable stents with drug-eluting nanofiber were developed to treat rabbit denuded arteries in this study. Biodegradable stents were fabricated using poly-L-lactide film following being cut and rolled into a cable-tie type stent. Additionally, drug-eluting biodegradable nanofiber tubes were electrospun from a solution containing poly (lactic-co-glycolic acid), rapamycin, and hexafluoroisopropanol, and then mounted onto the stents. The fabricated rapamycin-eluting cable-tie stents exhibited excellent mechanical properties on evaluation of compression test and collapse pressure, and less than 8% weight loss following being immersed in phosphate-buffered saline for 16 weeks. Furthermore, the biodegradable stents delivered high rapamycin concentrations for over 4 weeks and achieved substantial reductions in intimal hyperplasia associated with elevated heme oxygenase-1 and calponin level on the denuded rabbit arteries during 6 months of follow-up. The drug-eluting cable-tie type stents developed in this study might have high potential impacts for the local drug delivery to treat various vascular diseases.
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Affiliation(s)
- Cheng-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Ming-Jer Hsieh
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Shang-Hung Chang
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chang-Lin Chiang
- Department of Mechanical Engineering, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Lung Fan
- Department of Mechanical Engineering, Chang Gung University, Taoyuan, Taiwan
| | - Shih-Jung Liu
- Department of Mechanical Engineering, Chang Gung University, Taoyuan, Taiwan.
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.
| | - Wei-Jan Chen
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chao-Jan Wang
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Ming-Yi Hsu
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Kuo-Chun Hung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chung-Chuan Chou
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Po-Cheng Chang
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taipei, Taiwan
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21
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Smyth LA, Meader L, Xiao F, Woodward M, Brady HJM, Lechler R, Lombardi G. Constitutive expression of the anti-apoptotic Bcl-2 family member A1 in murine endothelial cells leads to transplant tolerance. Clin Exp Immunol 2017; 188:219-225. [PMID: 28120329 DOI: 10.1111/cei.12931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2017] [Indexed: 11/26/2022] Open
Abstract
Anti-apoptotic genes, including those of the Bcl-2 family, have been shown to have dual functionality inasmuch as they inhibit cell death but also regulate inflammation. Several anti-apoptotic molecules have been associated with endothelial cell (EC) survival following transplantation; however, their exact role has yet to be elucidated in respect to controlling inflammation. In this study we created mice expressing murine A1 (Bfl-1), a Bcl-2 family member, under the control of the human intercellular adhesion molecule 2 (ICAM-2) promoter. Constitutive expression of A1 in murine vascular ECs conferred protection from cell death induced by the proinflammatory cytokine tumour necrosis factor (TNF)-α. Importantly, in a mouse model of heart allograft transplantation, expression of A1 in vascular endothelium increased survival in the absence of CD8+ T cells. Better graft outcome in mice receiving an A1 transgenic heart correlated with a reduced immune infiltration, which may be related to increased EC survival and reduced expression of adhesion molecules on ECs. In conclusion, constitutive expression of the anti-apoptotic molecule Bfl1 (A1) in murine vascular ECs leads to prolonged allograft survival due to modifying inflammation.
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Affiliation(s)
- L A Smyth
- Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK.,School of Health, Sports and Biosciences, University of East London, London, UK
| | - L Meader
- Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - F Xiao
- Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - M Woodward
- Peter Gorer Department of Immunobiology, Borough Wing, Guy's Hospital, King's College, London, UK
| | - H J M Brady
- Immunology and Infection Section, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College, London, UK
| | - R Lechler
- Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - G Lombardi
- Medical Research Council (MRC) Centre for Transplantation, King's College London, London, UK, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
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22
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Liu L, Gao H, Hong C, He C, Pan D, Dai Y, Hara H, Cooper DKC, Li Z, Cai Z, Mou L. Klotho attenuated antibody-mediated porcine endothelial cell activation and injury. Xenotransplantation 2017; 24. [PMID: 28130792 DOI: 10.1111/xen.12286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 09/27/2016] [Accepted: 12/07/2016] [Indexed: 11/30/2022]
Abstract
Long-term success in pig-to-primate xenotransplantation is currently hampered by acute vascular rejection (AVR), characterized by endothelial cell (EC) activation and injury. Klotho has anti-apoptotic, anti-inflammatory effects on EC and protects EC against reactive oxygen species, rendering klotho a promising molecule to control AVR. In this study, porcine ECs were pre-incubated with klotho and then exposed to xenoreactive antibodies and complement. Real-time PCR revealed that klotho suppressed antibody-induced pro-inflammatory gene expression of VCAM-1 and IL-1α. NF-κB activation, IκBα phosphorylation, was also attenuated by klotho administration. Furthermore, klotho induced in porcine EC resistance against complement-dependent cytotoxicity. Accompanying this change, the binding of IgG and IgM xenoreactive antibodies to porcine EC was decreased and the expression of anti-inflammatory gene HO-1 was upregulated. These findings indicated that klotho protein protected porcine EC from activation and injury caused by binding of xenoreactive antibodies and was a promising candidate molecule in a multitransgenic pig strategy for xenotransplantation.
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Affiliation(s)
- Lu Liu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hanchao Gao
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chungu Hong
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Chen He
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Dengke Pan
- Key Laboratory of Farm Animal Genetic Resource and Germplasm Innovation of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Shenzhen, China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Hidetaka Hara
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - David K C Cooper
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Zesong Li
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
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23
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Wang L, Kumar S, Dahiya S, Wang F, Wu J, Newick K, Han R, Samanta A, Beier UH, Akimova T, Bhatti TR, Nicholson B, Kodrasov MP, Agarwal S, Sterner DE, Gu W, Weinstock J, Butt TR, Albelda SM, Hancock WW. Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity. EBioMedicine 2016; 13:99-112. [PMID: 27769803 PMCID: PMC5264272 DOI: 10.1016/j.ebiom.2016.10.018] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 10/04/2016] [Accepted: 10/13/2016] [Indexed: 02/08/2023] Open
Abstract
Foxp3 + T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or “secondary” modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3 + Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.
Conditional deletion of Usp7 in Foxp3 + Treg cells causes rapidly lethal autoimmunity. Pharmacologic inhibition of Usp7 impairs Treg but not conventional T cell function.
Usp7 targeting alone, or in conjunction with other therapies, promotes anti-tumor immunity.
T-regulatory (Treg) cells are essential to regulation of the immune system, and are characterized by their expression of the transcription factor, Foxp3. Foxp3 is subject to ubiquitination and degradation via the proteasome. We now show that the deubiquitinase, Usp7, is a key regulator of Foxp3 + Treg biology through controlling levels of the histone acetyltransferase, Tip60 and, to a lesser extent, Foxp3. Gene deletion or pharmacologic inhibition of Usp7 impairs Treg but not conventional T cell functions. The pharmacologic targeting of Usp7 alone, or in conjunction with additional therapeutic strategies, is of significant benefit in promoting host anti-tumor immunity.
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Affiliation(s)
- Liqing Wang
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Satinder Dahiya
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Feng Wang
- Progenra, Inc., Malvern, PA 19355, USA
| | - Jian Wu
- Progenra, Inc., Malvern, PA 19355, USA
| | - Kheng Newick
- Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA
| | - Rongxiang Han
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Arabinda Samanta
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ulf H Beier
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA19104, USA
| | - Tatiana Akimova
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tricia R Bhatti
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | | | | | - Wei Gu
- Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | | | | | - Steven M Albelda
- Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA19104, USA
| | - Wayne W Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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24
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Wagener FADTG, Immenschuh S. Editorial: Molecular Mechanisms Protecting against Tissue Injury. Front Pharmacol 2016; 7:272. [PMID: 27621704 PMCID: PMC5002404 DOI: 10.3389/fphar.2016.00272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/10/2016] [Indexed: 12/25/2022] Open
Affiliation(s)
- Frank A D T G Wagener
- Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center Nijmegen, Netherlands
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School Hannover, Germany
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25
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Mason JC. Cytoprotective pathways in the vascular endothelium. Do they represent a viable therapeutic target? Vascul Pharmacol 2016; 86:41-52. [PMID: 27520362 DOI: 10.1016/j.vph.2016.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/08/2016] [Indexed: 12/28/2022]
Abstract
The vascular endothelium is a critical interface, which separates the organs from the blood and its contents. The endothelium has a wide variety of functions and maintenance of endothelial homeostasis is a multi-dimensional active process, disruption of which has potentially deleterious consequences if not reversed. Vascular injury predisposes to endothelial apoptosis, dysfunction and development of atherosclerosis. Endothelial dysfunction is an end-point, a central feature of which is increased ROS generation, a reduction in endothelial nitric oxide synthase and increased nitric oxide consumption. A dysfunctional endothelium is a common feature of diseases including rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus and chronic renal impairment. The endothelium is endowed with a variety of constitutive and inducible mechanisms that act to minimise injury and facilitate repair. Endothelial cytoprotection can be enhanced by exogenous factors such as vascular endothelial growth factor, prostacyclin and laminar shear stress. Target genes include endothelial nitric oxide synthase, heme oxygenase-1, A20 and anti-apoptotic members of the B cell lymphoma protein-2 family. In light of the importance of endothelial function, and the link between its disruption and the risk of atherothrombosis, interest has focused on therapeutic conditioning and reversal of endothelial dysfunction. A detailed understanding of cytoprotective signalling pathways, their regulation and target genes is now required to identify novel therapeutic targets. The ultimate aim is to add vasculoprotection to current therapeutic strategies for systemic inflammatory diseases, in an attempt to reduce vascular injury and prevent or retard atherogenesis.
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Affiliation(s)
- Justin C Mason
- Vascular Science, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.
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26
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Li Z, Li Y, Zhang T, Miao W, Su G. Comparison of the influence of ticagrelor and clopidogrel on inflammatory biomarkers and vascular endothelial function for patients with ST-segment elevation myocardial infarction receiving emergency percutaneous coronary intervention: study protocol for a randomized controlled trial. Trials 2016; 17:75. [PMID: 26865043 PMCID: PMC4750211 DOI: 10.1186/s13063-016-1168-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 01/11/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The Platelet Inhibition and Patient Outcomes (PLATO, Eur J Prev Cardiol 22(6):734-42, 2015) trial shows that, in patients who have an acute coronary syndrome, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death, but the reason is still uncertain. Both inflammation and vascular endothelian cell dysfunction play important roles in the pathophysiology of atherosclerotic plaques, but whether ticagrelor has superior anti-inflammatory effect and can improve vascular endothelial cell function to a great extent is unknown. METHODS/DESIGN Patients with STEMI who are scheduled to undergo emergency percutaneous coronary intervention (PCI) will be randomly assigned to receive a loading dose of ticagrelor 180 mg as the treatment group or clopidogrel 600 mg as the control group. After PCI, the treatment group will be treated with ticagrelor 90 mg twice daily while the control group will be treated with clopidogrel 75 mg once daily. The vascular endothelial function will be tested by circulating endothelial cells, and levels of inflammation will be tested by CD40 ligand (CD40L), high sensitivity C-reactive protein (hsCRP) and P-selectin. The estimated enrollment sample size will be 350 patients, including 175 in the treatment group and 175 in the control group. DISCUSSION This study will compare the influence of ticagrelor and clopidogrel on inflammatory biomarkers and vascular endothelial function firstly for STEMI patients receiving emergency PCI and will provide evidence to identify whether ticagrelor inhibits inflammation and improves vascular endothelial cell function to a greater extent than clopidogrel or not. TRIAL REGISTRATION This trial was registered with Clinicaltrials.gov (identifier: NCT02123004) on 20 April 2014.
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Affiliation(s)
- Zhenhua Li
- Department of Cardiology, Jinan Central Hospital, Shandong, China.
| | - Yueyan Li
- Department of Cardiology, Jinan Central Hospital, Shandong, China.
| | - Tao Zhang
- Department of Orthopedics, Jinan Central Hospital, Shandong, China.
| | - Wei Miao
- Department of Cardiology, Jinan Central Hospital, Shandong, China.
| | - Guohai Su
- Department of Cardiology, Jinan Central Hospital, Shandong, China.
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27
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Yang H, Zhao P, Tian S. Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway. J Diabetes Res 2016; 2016:9128050. [PMID: 26824050 PMCID: PMC4707324 DOI: 10.1155/2016/9128050] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 09/29/2015] [Accepted: 09/29/2015] [Indexed: 12/30/2022] Open
Abstract
Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKβ/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKβ/AMPK pathway-dependent.
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Affiliation(s)
- Huabing Yang
- School of Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, China
- Department of Medicine and Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Pengjun Zhao
- Pediatric Heart Center, Children's Hospital of Fudan University, Shanghai 200032, China
| | - Shiliu Tian
- Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
- *Shiliu Tian:
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28
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Patel SR, Copland IB, Garcia MA, Metz R, Galipeau J. Human mesenchymal stromal cells suppress T-cell proliferation independent of heme oxygenase-1. Cytotherapy 2015; 17:382-91. [PMID: 25595329 DOI: 10.1016/j.jcyt.2014.11.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 11/17/2014] [Accepted: 11/27/2014] [Indexed: 01/14/2023]
Abstract
Mesenchymal stromal cells deploy immune suppressive properties amenable for use as cell therapy for inflammatory disorders. It is now recognized that mesenchymal stromal cells necessitate priming with an inflammatory milieu, in particular interferon-γ, to exert augmented immunosuppressive effects. It has been recently suggested that the heme-catabolizing enzyme heme oxygenase-1 is an essential component of the mesenchymal stromal cell-driven immune suppressive response. Because mesenchymal stromal cells upregulate indoleamine 2,3-dioxygenase expression on interferon-γ priming and indoleamine 2,3-dioxygenase requires heme as a cofactor for optimal catabolic function, we investigated the potential antagonism of heme oxygenase-1 activity on indoleamine 2, 3-dioxygenase and the impact on mesenchymal stromal cell immune plasticity. We herein sought to evaluate the molecular genetic effect of cytokine priming on human mesenchymal stromal cell heme oxygenase-1 expression and its functional role in differentially primed mesenchymal stromal cells. Contrary to previous reports, messenger RNA and protein analyses demonstrated that mesenchymal stromal cells derived from normal subjects (n = 6) do not express heme oxygenase-1 at steady state or after interferon-γ, tumor necrosis factor-α, and/or transforming growth factor-β priming. Pharmacological inhibition of heme oxygenase-1 with the use of tin protoporphyrin did not significantly abrogate the ability of mesenchymal stromal cells to suppress T-cell proliferation in vitro. Overall, these results unequivocally demonstrate that under steady state and after cytokine priming, human mesenchymal stromal cells immunoregulate T-cell proliferation independent of heme oxygenase-1.
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Affiliation(s)
- Seema R Patel
- Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA
| | - Ian B Copland
- Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA
| | - Marco A Garcia
- Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA
| | - Richard Metz
- NewLink Genetics Inc, Plymouth Meeting, Pennsylvania, USA
| | - Jacques Galipeau
- Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
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29
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von Rossum A, Laher I, Choy JC. Immune-mediated vascular injury and dysfunction in transplant arteriosclerosis. Front Immunol 2015; 5:684. [PMID: 25628623 PMCID: PMC4290675 DOI: 10.3389/fimmu.2014.00684] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 12/18/2014] [Indexed: 12/16/2022] Open
Abstract
Solid organ transplantation is the only treatment for end-stage organ failure but this life-saving procedure is limited by immune-mediated rejection of most grafts. Blood vessels within transplanted organs are targeted by the immune system and the resultant vascular damage is a main contributor to acute and chronic graft failure. The vasculature is a unique tissue with specific immunological properties. This review discusses the interactions of the immune system with blood vessels in transplanted organs and how these interactions lead to the development of transplant arteriosclerosis, a leading cause of heart transplant failure.
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Affiliation(s)
- Anna von Rossum
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
| | - Ismail Laher
- Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia , Vancouver, BC , Canada
| | - Jonathan C Choy
- Department of Molecular Biology and Biochemistry, Simon Fraser University , Burnaby, BC , Canada
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30
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Wong ML, Griffiths LG. Immunogenicity in xenogeneic scaffold generation: antigen removal vs. decellularization. Acta Biomater 2014; 10:1806-16. [PMID: 24486910 DOI: 10.1016/j.actbio.2014.01.028] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 12/15/2013] [Accepted: 01/23/2014] [Indexed: 12/11/2022]
Abstract
Decades of research have been undertaken towards the goal of tissue engineering using xenogeneic scaffolds. The primary advantages associated with use of xenogeneic tissue-derived scaffolds for in vitro development of replacement tissues and organs stem from the inherent extracellular matrix (ECM) composition and architecture. Native ECM possesses appropriate mechanical properties for physiological function of the biomaterial and signals for cell binding, growth and differentiation. Additionally, xenogeneic tissue is readily available. However, translation of xenogeneic scaffold-derived engineered tissues or organs into clinical therapies requires xenoantigenicity of the material to be adequately addressed prior to implantation. Failure to achieve this goal will result in a graft-specific host immune rejection response, jeopardizing in vivo survival of the resultant scaffold, tissue or organ. This review explores (i) the appropriateness of scaffold acellularity as an outcome measure for assessing reduction of the immunological barriers to the use of xenogeneic scaffolds for tissue engineering applications and (ii) the need for tissue engineers to strive for antigen removal during xenogeneic scaffold generation.
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Affiliation(s)
- Maelene L Wong
- Department of Veterinary Medicine: Medicine and Epidemiology, University of California, Davis, One Shields Ave., Davis, CA 95616, USA; Department of Biomedical Engineering, University of California, Davis, One Shields Ave., Davis, CA 95616, USA
| | - Leigh G Griffiths
- Department of Veterinary Medicine: Medicine and Epidemiology, University of California, Davis, One Shields Ave., Davis, CA 95616, USA.
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31
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Mitchell RN. Learning from rejection: What transplantation teaches us about (other) vascular pathologies. J Autoimmun 2013; 45:80-9. [DOI: 10.1016/j.jaut.2013.05.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 05/30/2013] [Indexed: 01/03/2023]
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32
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Long-term prevention of chronic allograft rejection by regulatory T-cell immunotherapy involves host Foxp3-expressing T cells. Blood 2013; 121:4303-10. [DOI: 10.1182/blood-2012-08-452037] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Key Points
Administration of donor-specific regulatory T cells prevents chronic rejection of BM and skin allografts in the mouse. Injected regulatory T cells induce the emergence of host regulatory T cells with similar specificity thus ensuring persistence of tolerance.
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33
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Proinflammatory responses of heme in alveolar macrophages: repercussion in lung hemorrhagic episodes. Mediators Inflamm 2013; 2013:946878. [PMID: 23690673 PMCID: PMC3652176 DOI: 10.1155/2013/946878] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 03/04/2013] [Accepted: 03/19/2013] [Indexed: 12/14/2022] Open
Abstract
Clinical and experimental observations have supported the notion that free heme released during hemorrhagic and hemolytic episodes may have a major role in lung inflammation. With alveolar macrophages (AM) being the main line of defense in lung environments, the influence of free heme on AM activity and function was investigated. We observed that heme in a concentration range found during hemolytic episodes (3–30 μM) elicits AM to present a proinflammatory profile, stimulating reactive oxygen species (ROS) and nitric oxide (NO) generation and inducing IL-1β, IL-6, and IL-10 secretion. ROS production is NADPH oxidase-dependent, being inhibited by DPI and apocynin, and involves p47 subunit phosphorylation. Furthermore, heme induces NF-κB nuclear translocation, iNOS, and also HO-1 expression. Moreover, AM stimulated with free heme show enhanced phagocytic and bactericidal activities. Taken together, the data support a dual role for heme in the inflammatory response associated with lung hemorrhage, acting as a proinflammatory molecule that can either act as both an adjuvant of the innate immunity and as an amplifier of the inflammatory response, leading tissue injury. The understanding of heme effects on pulmonary inflammatory processes can lead to the development of new strategies to ameliorate tissue damage associated with hemorrhagic episodes.
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34
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Bakdash G, Sittig SP, van Dijk T, Figdor CG, de Vries IJM. The nature of activatory and tolerogenic dendritic cell-derived signal II. Front Immunol 2013; 4:53. [PMID: 23450201 PMCID: PMC3584294 DOI: 10.3389/fimmu.2013.00053] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 02/11/2013] [Indexed: 12/31/2022] Open
Abstract
Dendritic cells (DCs) are central in maintaining the intricate balance between immunity and tolerance by orchestrating adaptive immune responses. Being the most potent antigen presenting cells, DCs are capable of educating naïve T cells into a wide variety of effector cells ranging from immunogenic CD4+ T helper cells and cytotoxic CD8+ T cells to tolerogenic regulatory T cells. This education is based on three fundamental signals. Signal I, which is mediated by antigen/major histocompatibility complexes binding to antigen-specific T cell receptors, guarantees antigen specificity. The co-stimulatory signal II, mediated by B7 family molecules, is crucial for the expansion of the antigen-specific T cells. The final step is T cell polarization by signal III, which is conveyed by DC-derived cytokines and determines the effector functions of the emerging T cell. Although co-stimulation is widely recognized to result from the engagement of T cell-derived CD28 with DC-expressed B7 molecules (CD80/CD86), other co-stimulatory pathways have been identified. These pathways can be divided into two groups based on their impact on primed T cells. Whereas pathways delivering activatory signals to T cells are termed co-stimulatory pathways, pathways delivering tolerogenic signals to T cells are termed co-inhibitory pathways. In this review, we discuss how the nature of DC-derived signal II determines the quality of ensuing T cell responses and eventually promoting either immunity or tolerance. A thorough understanding of this process is instrumental in determining the underlying mechanism of disorders demonstrating distorted immunity/tolerance balance, and would help innovating new therapeutic approaches for such disorders.
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Affiliation(s)
- Ghaith Bakdash
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre Nijmegen, Netherlands
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Djuric Z, Kashif M, Fleming T, Muhammad S, Piel D, von Bauer R, Bea F, Herzig S, Zeier M, Pizzi M, Isermann B, Hecker M, Schwaninger M, Bierhaus A, Nawroth PP. Targeting activation of specific NF-κB subunits prevents stress-dependent atherothrombotic gene expression. Mol Med 2012; 18:1375-86. [PMID: 23114885 DOI: 10.2119/molmed.2012.00282] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 10/23/2012] [Indexed: 11/06/2022] Open
Abstract
Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-κB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein(-/-) (ApoE(-/-)) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease.
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Affiliation(s)
- Zdenka Djuric
- Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
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Simon T, Pogu S, Tardif V, Rigaud K, Rémy S, Piaggio E, Bach JM, Anegon I, Blancou P. Carbon monoxide-treated dendritic cells decrease β1-integrin induction on CD8⁺ T cells and protect from type 1 diabetes. Eur J Immunol 2012; 43:209-18. [PMID: 23065740 DOI: 10.1002/eji.201242684] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 09/21/2012] [Accepted: 10/08/2012] [Indexed: 01/12/2023]
Abstract
Carbon monoxide (CO) treatment improves pathogenic outcome of autoimmune diseases by promoting tolerance. However, the mechanism behind this protective tolerance is not yet defined. Here, we show in a transgenic mouse model for autoimmune diabetes that ex vivo gaseous CO (gCO)-treated DCs loaded with pancreatic β-cell peptides protect mice from disease. This protection is peptide-restricted, independent of IL-10 secretion by DCs and of CD4(+) T cells. Although no differences were observed in autoreactive CD8(+) T-cell function from gCO-treated versus untreated DC-immunized groups, gCO-treated DCs strongly inhibited accumulation of autoreactive CD8(+) T cells in the pancreas. Interestingly, induction of β1-integrin was curtailed when CD8(+) T cells were primed with gCO-treated DCs, and the capacity of these CD8(+) T cells to lyse isolated islet was dramatically impaired. Thus, immunotherapy using CO-treated DCs appears to be an original strategy to control autoimmune disease.
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Conlon TM, Cole JL, Motallebzadeh R, Harper I, Callaghan CJ, Bolton EM, Bradley JA, Saeb-Parsy K, Pettigrew GJ. Unlinked memory helper responses promote long-lasting humoral alloimmunity. THE JOURNAL OF IMMUNOLOGY 2012; 189:5703-12. [PMID: 23162131 DOI: 10.4049/jimmunol.1202257] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Essential help for long-lived alloantibody responses is theoretically provided only by CD4 T cells that recognize target alloantigen, processed and presented by the allospecific B cell. We demonstrate that in an alloresponse to multiple MHC disparities, cognate help for class-switched alloantibody may also be provided by CD4 T cells specific for a second "helper" alloantigen. This response was much shorter-lived than when help was provided conventionally, by Th cell recognition of target alloantigen. Nevertheless, long-lasting humoral alloimmunity developed when T cell memory against the helper alloantigen was first generated. Costimulatory blockade abrogated alloantibody produced through naive Th cell recognition of target alloantigen but, crucially, blockade was ineffective when help was provided by memory responses to the accessory helper alloantigen. These results suggest that memory Th cell responses against previously encountered graft alloantigen may be the dominant mechanism for providing help to generate new specificities of alloantibody in transplant patients receiving immunosuppression.
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Affiliation(s)
- Thomas M Conlon
- Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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Callaghan CJ, Win TS, Motallebzadeh R, Conlon TM, Chhabra M, Harper I, Sivaganesh S, Bolton EM, Bradley JA, Brownlie RJ, Smith KGC, Pettigrew GJ. Regulation of allograft survival by inhibitory FcγRIIb signaling. THE JOURNAL OF IMMUNOLOGY 2012; 189:5694-702. [PMID: 23150718 DOI: 10.4049/jimmunol.1202084] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Fcγ receptors (FcγR) provide important immunoregulation. Targeting inhibitory FcγRIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. FcγRIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked FcγRIIb expression (FcγRIIb(-/-)) or overexpressed FcγRIIb on B cells (B cell transgenic [BTG]). Acute heart allograft rejection occurred at the same tempo in FcγRIIb(-/-) C57BL/6 (B6) recipients as wild type recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II-mismatched bm12 cardiac allografts was accelerated in FcγRIIb(-/-) mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited and rejection was delayed in BTG recipients. Similarly, whereas MHC class I-mismatched B6.K(d) hearts survived indefinitely and remained disease free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in FcγRIIb(-/-) recipients. Notably, FcγRIIb-mediated inhibition of B6.K(d) heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.K(d)-specific CD4 T cells. Thus, inhibitory FcγRIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes FcγRIIb-mediated inhibition of the effector B cell population. Immunomodulation of FcγRIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging transplant survival.
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Affiliation(s)
- Chris J Callaghan
- Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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Gene transfer of heme oxygenase-1 using an adeno-associated virus serotype 6 vector prolongs cardiac allograft survival. J Transplant 2012; 2012:740653. [PMID: 23125915 PMCID: PMC3480008 DOI: 10.1155/2012/740653] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Revised: 09/07/2012] [Accepted: 09/07/2012] [Indexed: 11/18/2022] Open
Abstract
Introduction. Allograft survival can be prolonged by overexpression of cytoprotective genes such as heme oxygenase-1 (HO-1). Modifications in vector design and delivery have provided new opportunities to safely and effectively administer HO-1 into the heart prior to transplantation to improve long-term graft outcome. Methods. HO-1 was delivered to the donor heart using an adeno-associated virus vector (AAV) with a pseudotype 6 capsid and vascular endothelial growth factor (VEGF) to enhance myocardial tropism and microvascular permeability. Survival of mouse cardiac allografts, fully or partially mismatched at the MHC, was determined with and without cyclosporine A. Intragraft cytokine gene expression was examined by PCR.
Results. The use of AAV6 to deliver HO-1 to the donor heart, combined with immunosuppression, prolonged allograft survival by 55.3% when donor and recipient were completely mismatched at the MHC and by 94.6% if partially mismatched. The combination of gene therapy and immunosuppression was more beneficial than treatment with either AAV6-HO-1 or CsA alone. IL-17a, b, e and f were induced in the heart at rejection.
Conclusions. Pretreatment of cardiac allografts with AAV6-HO-1 plus cyclosporine A prolonged graft survival. HO-1 gene therapy represents a beneficial adjunct to immunosuppressive therapy in cardiac transplantation.
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Ohta R, Tanaka N, Nakanishi K, Kamei N, Nakamae T, Izumi B, Fujioka Y, Ochi M. Heme oxygenase-1 modulates degeneration of the intervertebral disc after puncture in Bach 1 deficient mice. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2012; 21:1748-57. [PMID: 22832873 DOI: 10.1007/s00586-012-2442-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 07/06/2012] [Accepted: 07/07/2012] [Indexed: 01/08/2023]
Abstract
PURPOSE Intervertebral disc degeneration is considered to be a major feature of low back pain. Furthermore, oxidative stress has been shown to be an important factor in degenerative diseases such as osteoarthritis and is considered a cause of intervertebral disc degeneration. The purpose of this study was to clarify the correlation between oxidative stress and intervertebral disc degeneration using Broad complex-Tramtrack-Bric-a-brac and cap'n'collar homology 1 deficient (Bach 1-/-) mice which highly express heme oxygenase-1 (HO-1). HO-1 protects cells from oxidative stress. METHODS Caudal discs of 12-week-old and 1-year-old mice were evaluated as age-related models. Each group and period, 5 mice (a total of 20 mice, a total of 20 discs) were evaluated as age-related model. C9-C10 caudal discs in 12-week-old Bach 1-/- and wild-type mice were punctured using a 29-gauge needle as annulus puncture model. Each group and period, 5 mice (a total of 60 mice, a total of 60 discs) were evaluated. The progress of disc degeneration was evaluated at pre-puncture, 1, 2, 4, 8 and 12 weeks post-puncture. Radiographic, histologic and immunohistologic analysis were performed to compare between Bach 1-/- and wild-type mice. RESULTS In the age-related model, there were no significant differences between Bach 1-/- and wild-type mice radiologically and histologically. However, in the annulus puncture model, histological scoring revealed significant difference at 8 and 12 weeks post-puncture. The number of HO-1 positive cells was significantly greater in Bach 1-/- mice at every period. The apoptosis rate was significantly lower at 1 and 2 weeks post-puncture in Bach 1-/- mice. CONCLUSIONS Oxidative stress prevention may avoid the degenerative process of the intervertebral disc after puncture, reducing the number of apoptosis cells. High HO-1 expression may also inhibit oxidative stress and delay the process of intervertebral disc degeneration.
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Affiliation(s)
- Ryo Ohta
- Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi, Hiroshima, 734-8551, Japan,
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Araujo JA, Zhang M, Yin F. Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol 2012. [PMID: 22833723 DOI: 10.3389/fphar.2012.00119.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low-density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1) is a Nrf2-regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of HO, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide, and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative, and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO-1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This suggests that a potential intervention on HO-1 or its byproducts may need to take into account any potential alteration in the status of Nrf2 activation. This article reviews the available evidence that supports the antiatherogenic role of HO-1 as well as the potential pathways and mechanisms mediating vascular protection.
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Affiliation(s)
- Jesus A Araujo
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, CA, USA
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Araujo JA, Zhang M, Yin F. Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front Pharmacol 2012; 3:119. [PMID: 22833723 PMCID: PMC3400084 DOI: 10.3389/fphar.2012.00119] [Citation(s) in RCA: 339] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 06/06/2012] [Indexed: 12/14/2022] Open
Abstract
Atherosclerosis is an inflammatory process of the vascular wall characterized by the infiltration of lipids and inflammatory cells. Oxidative modifications of infiltrating low-density lipoproteins and induction of oxidative stress play a major role in lipid retention in the vascular wall, uptake by macrophages and generation of foam cells, a hallmark of this disorder. The vasculature has a plethora of protective resources against oxidation and inflammation, many of them regulated by the Nrf2 transcription factor. Heme oxygenase-1 (HO-1) is a Nrf2-regulated gene that plays a critical role in the prevention of vascular inflammation. It is the inducible isoform of HO, responsible for the oxidative cleavage of heme groups leading to the generation of biliverdin, carbon monoxide, and release of ferrous iron. HO-1 has important antioxidant, antiinflammatory, antiapoptotic, antiproliferative, and immunomodulatory effects in vascular cells, most of which play a significant role in the protection against atherogenesis. HO-1 may also be an important feature in macrophage differentiation and polarization to certain subtypes. The biological effects of HO-1 are largely attributable to its enzymatic activity, which can be conceived as a system with three arms of action, corresponding to its three enzymatic byproducts. HO-1 mediated vascular protection may be due to a combination of systemic and vascular local effects. It is usually expressed at low levels but can be highly upregulated in the presence of several proatherogenic stimuli. The HO-1 system is amenable for use in the development of new therapies, some of them currently under experimental and clinical trials. Interestingly, in contrast to the HO-1 antiatherogenic actions, the expression of its transcriptional regulator Nrf2 leads to proatherogenic effects instead. This suggests that a potential intervention on HO-1 or its byproducts may need to take into account any potential alteration in the status of Nrf2 activation. This article reviews the available evidence that supports the antiatherogenic role of HO-1 as well as the potential pathways and mechanisms mediating vascular protection.
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Affiliation(s)
- Jesus A. Araujo
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA
| | - Min Zhang
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA
| | - Fen Yin
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of CaliforniaLos Angeles, CA, USA
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Valenzuela NM, Reed EF. The link between major histocompatibility complex antibodies and cell proliferation. Transplant Rev (Orlando) 2011; 25:154-66. [PMID: 21803559 PMCID: PMC3177030 DOI: 10.1016/j.trre.2011.04.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2010] [Revised: 02/08/2011] [Accepted: 04/26/2011] [Indexed: 11/25/2022]
Abstract
Experimental evidence indicates that donor-specific antibodies targeting major histocompatibility complex classes I and II molecules can elicit the key features of transplant vasculopathy by acting on the graft vasculature in 3 ways: directly activating proliferative, prosurvival, and migratory signaling in the target endothelial and smooth muscle cells; increasing expression of mitogenic factors in vascular endothelial cells, creating a potential proliferative autocrine loop; and promoting recruitment of inflammatory cells that produce mitogenic factors and elicit chronic inflammation, proliferation, and fibrosis. Here, we review the experimental literature showing the complement and Fc-independent effects of major histocompatibility complex classes I and II antibodies on graft vascular cells that may directly contribute to the proliferative aspect of transplant vasculopathy.
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Affiliation(s)
- Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1652, USA
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Abstract
HO-1 (haem oxygenase-1) is a ubiquitously expressed inducible enzyme degrading haem to CO, biliverdin and Fe2+. Its activation reduces oxidative stress in cells and inhibits inflammation, both due to removal of haem and because of the biological activity of HO-1 products. CO may act similarly to NO, activating soluble guanylate cyclase and elevating cGMP production. It inhibits platelet aggregation, reduces leucocyte adhesion, decreases apoptosis and lowers the production of some pro-inflammatory cytokines. Biliverdin is converted into bilirubin by biliverdin reductase, and both compounds are potent antioxidants, free radical scavengers and inhibitors of the complement cascade. Iron ions can be potentially toxic, increasing the generation of hydroxyl radicals, but simultaneous induction of ferritin and activation of the Fe-ATPase iron transporter protects cells from oxidative stress. Importantly, basal and induced expression of HO-1 is very variable in the human population because of the highly polymorphic (GT)n fragment in the promoter, which may have clinical relevance. The recognized roles of HO-1 are far beyond cytoprotection. The enzyme is important in the regulation of cell proliferation, differentiation and apoptosis. Its activity improves neovascularization, attenuates inflammation and modulates the immune response, thereby influencing carcinogenesis, wound healing, transplant survival and the progression of cardiovascular diseases. Recent results indicate that HO-1 may also act through the regulation of microRNAs, which suggests a much broader involvement of HO-1 in the modulation of cell functions and offers a potential explanation for some well-known activities whose mechanism has hitherto been unclear.
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Durante W. Protective role of heme oxygenase-1 against inflammation in atherosclerosis. Front Biosci (Landmark Ed) 2011; 16:2372-88. [PMID: 21622183 DOI: 10.2741/3860] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting step in the metabolism of free heme into equimolar amounts of ferrous iron, carbon monoxide (CO), and biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. HO-1 has recently been identified as a promising therapeutic target in the treatment of vascular inflammatory disease, including atherosclerosis. HO-1 represses inflammation by removing the pro-inflammatory molecule heme and by generating CO and the bile pigments, biliverdin and bilirubin. These HO-1 reaction products are capable of blocking innate and adaptive immune responses by modifying the activation, differentiation, maturation, and/or polarization of numerous immune cells, including endothelial cells, monocytes/macrophages, dendritic cells, T lymphocytes, mast cells, and platelets. These cellular actions by CO and bile pigments result in diminished leukocyte recruitment and infiltration, and pro-inflammatory mediator production within atherosclerotic lesions. This review highlights the mechanisms by which HO-1 suppresses vascular inflammation in atherosclerosis, and explores possible therapeutic modalities by which HO-1 and its reaction products can be employed to ameliorate vascular inflammatory disease.
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Affiliation(s)
- William Durante
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, USA.
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Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol Cell Biol 2011; 31:2066-78. [PMID: 21444725 DOI: 10.1128/mcb.05155-11] [Citation(s) in RCA: 215] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Foxp3(+) T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3(+) Tregs express multiple histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression, and protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production and Treg suppression function but have limited nononcologic utility given their broad actions and various side effects. We show, using HDAC6-deficient mice and wild-type (WT) mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein heat shock protein 90 (HSP90). Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection.
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Katana E, Skoura L, Giakoustidis D, Takoudas D, Malisiovas N, Daniilidis M. Association between the heme oxygenase-1 promoter polymorphism and renal transplantation outcome in Greece. Transplant Proc 2011; 42:2479-85. [PMID: 20832528 DOI: 10.1016/j.transproceed.2010.05.161] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2010] [Accepted: 05/19/2010] [Indexed: 01/01/2023]
Abstract
BACKGROUND Heme oxygenase-1 (HO-1) is the enzyme that catabolizes heme into carbon monoxide, biliverdin, and free iron. The induction of this enzyme is an important cytoprotective mechanism, which occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli. HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. HO-1 inducibility is mainly modulated by a (GT)(n) repeat polymorphism in the promoter region, and has been shown that short repeats (S) are associated with greater upregulation of HO-1, compared with long repeats (L). In the present study we investigated the influence of this HO-1 gene polymorphism on clinical outcome after transplantation and on renal transplant function. METHODS DNA from 175 donor/recipient pairs who underwent transplantation between October 2002 and June 2007 was genotyped. We divided the HO-1 alleles into 2 subclasses, the S ≤ 27 repeats and L > 27 repeats. RESULTS There has been significant relevance between the genotype of the donor and the outcome of the graft, as far as recipients with normal graft function and recipients with deteriorated graft function are concerned (P = .021). In patients with normal graft function, grafts from L-homozygotes were found in 24%, whereas in patients with deteriorated function, grafts from L-homozygotes exhibited in higher rate (50%). Neither the donor's nor the recipient's polymorphism influenced the graft survival (log-rank test P = .228 for the donors and log-rank test P = 0.844 for the recipients). There was no evidence of a gene-dose effect on graft survival (P = .469). Recipients of allografts from S-carriers donors had significantly lower serum creatinine levels at 24 months compared with recipients of allografts from L-homozygotes donors (P = .016).
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Affiliation(s)
- E Katana
- Department of Genetics, Development, and Molecular Biology, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece.
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Cobbold SP. Future therapeutics for the induction of peripheral immune tolerance in autoimmune disease and organ transplantation. Immunotherapy 2011; 1:447-60. [PMID: 20635961 DOI: 10.2217/imt.09.9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Rodent models of transplantation and autoimmune disease have demonstrated that it is possible to induce lifelong and specific immunological tolerance to both self and graft antigens in the absence of any continued immunosuppression. If this situation could be achieved clinically, it would avoid many of the longer-term complications of immunosuppression, such as the increased risk of infection, cancer and other side effects, such as nephrotoxicity. In this review, we shall consider the interplay between regulatory T cells, dendritic cells and the tissue itself, and the resulting local protective mechanisms that are coordinated to maintain the tolerant state and an acquired local immune privilege. The current status of attempts to apply tolerogenic approaches to the clinical treatment of autoimmune diseases and to induce either tolerance to organ grafts or sufficient immune regulation so that conventional immunosuppression can be minimized will also be considered.
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Affiliation(s)
- Stephen P Cobbold
- University of Oxford, Therapeutic Immunology Group, Sir William Dunn School of Pathology, South Parks Road, Oxford, UK.
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Abstract
Heme oxygenase-1 (HO-1) metabolizes heme to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently metabolized to bilirubin by biliverdin reductase. HO-1 has recently emerged as a promising therapeutic target in the treatment of vascular disease. Pharmacological induction or gene transfer of HO-1 ameliorates vascular dysfunction in animal models of atherosclerosis, post-angioplasty restenosis, vein graft stenosis, thrombosis, myocardial infarction, and hypertension, while inhibition of HO-1 activity or gene deletion exacerbates these disorders. The vasoprotection afforded by HO-1 is largely attributable to its end products: CO and the bile pigments, biliverdin and bilirubin. These end products exert potent anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic actions. In addition, CO and bile pigments act to preserve vascular homeostasis at sites of arterial injury by influencing the proliferation, migration, and adhesion of vascular smooth muscle cells, endothelial cells, endothelial progenitor cells, or leukocytes. Several strategies are currently being developed to target HO-1 in vascular disease. Pharmacological induction of HO-1 by heme derivatives, dietary antioxidants, or currently available drugs, is a promising near-term approach, while HO-1 gene delivery is a long-term therapeutic goal. Direct administration of CO via inhalation or through the use of CO-releasing molecules and/or CO-sensitizing agents provides an attractive alternative approach in targeting HO-1. Furthermore, delivery of bile pigments, either alone or in combination with CO, presents another avenue for protecting against vascular disease. Since HO-1 and its products are potentially toxic, a major challenge will be to devise clinically effective therapeutic modalities that target HO-1 without causing any adverse effects.
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Affiliation(s)
- William Durante
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212, USA.
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Abstract
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism that converts heme to Fe++, carbon monoxide and biliverdin. HO-1 acts anti-inflammatory and modulates apoptosis in many pathological conditions. In transplantation, HO-1 is overexpressed in organs during brain death, when undergoing ischemic damage and rejection. However, intentionally induced, it ameliorates pathological processes like ischemia reperfusion injury, allograft, xenograft or islet rejection, facilitates donor specific tolerance and alleviates chronic allograft changes. We herein consistently summarize the huge amount of data on HO-1 and transplantation that have been generated in multiple laboratories during the last 15years and suggest possible clinical implications and applications for the near future.
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Affiliation(s)
- Robert Öllinger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria.
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