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Yang KY, Liao J, Ma Z, Tse HF, Lu L, Graca L, Lui KO. Single-cell transcriptomics of Treg reveals hallmarks and trajectories of immunological aging. J Leukoc Biol 2024; 115:19-35. [PMID: 37675661 DOI: 10.1093/jleuko/qiad104] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/25/2023] [Accepted: 08/09/2023] [Indexed: 09/08/2023] Open
Abstract
Age-related immunosenescence is characterized by progressive dysfunction of adaptive immune response and increased autoimmunity. Nevertheless, the impact of aging on CD4+ regulatory T cells that are master regulators of the immune system remains largely unclear. Here, we report cellular and molecular hallmarks of regulatory T cells derived from murine lymphoid and adipose tissues at 3, 18, and 24 mo of age, respectively, by analyzing their heterogeneity that displays dynamic changes in transcriptomic effector signatures at a single-cell resolution. Although the proportion of regulatory T cells among total Cd4+ T cells, as well as their expression levels of Foxp3, did not show any global change with time, we have identified 6 transcriptomically distinct clusters of regulatory T cells with cross-tissue conserved hallmarks of aging, including increased numbers of proinflammatory regulatory T cells, reduced precursor cells, increased immature and mature T follicular regulatory cells potentially supported by a metabolic switch from oxidative phosphorylation to glycolysis, a gradual loss of CD150hi regulatory T cells that support hematopoiesis, and increased adipose tissue-specific regulatory T cells that are associated with metabolic disease. To dissect the impact of immunosenescence on humoral immunity, we propose some potential mechanisms underlying T follicular regulatory cell-mediated dysfunction by interactome analysis on T follicular regulatory cells, T follicular helper cells, and B cells during aging. Lastly, spatiotemporal analysis further revealed trajectories of regulatory T-cell aging that demonstrate the most significant changes in marrow and adipose tissues that might contribute to the development of age-related immunosenescence and type 2 diabetes. Taken together, our findings could provide a better understanding of age-associated regulatory T-cell heterogeneity in lymphoid and adipose tissues, as well as regulatory T-cell hallmarks during progressive adaptation to aging that could be therapeutically targeted for rejuvenating the aging immune system in the future.
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Affiliation(s)
- Kevin Y Yang
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China
- Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, China
| | - Jinyue Liao
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China
| | - Zhangjing Ma
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China
| | - Hung Fat Tse
- Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, China
| | - Liwei Lu
- Department of Pathology, Queen Mary Hospital, The University of Hong Kong, 102 Pok Fu Lam Road, Hong Kong, China
| | - Luis Graca
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Edifício Egas Moniz, Avenida Professor Egas Moniz, 1649-028 Lisboa, Portugal
| | - Kathy O Lui
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China
- Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, N.T., Hong Kong, China
- Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10 2nd Yuexin Road, Nanshan District, Shenzhen, China
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Vaikunthanathan T, Landmann E, Correa DM, Romano M, Trevelin SC, Peng Q, Crespo E, Corrado M, Lozano JJ, Pearce EL, Perpinan E, Zoccarato A, Siew L, Edwards-Hicks J, Khan R, Luu NT, Thursz MR, Newsome PN, Martinez-Llordella M, Shah N, Lechler RI, Shah AM, Sanchez-Fueyo A, Lombardi G, Safinia N. Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease. EBioMedicine 2023; 95:104778. [PMID: 37657135 PMCID: PMC10480539 DOI: 10.1016/j.ebiom.2023.104778] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/15/2023] [Accepted: 08/15/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. METHODS The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. FINDINGS Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. INTERPRETATION Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. FUNDING This study was funded by the Wellcome Trust (211113/A/18/Z).
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Affiliation(s)
- Trishan Vaikunthanathan
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Emmanuelle Landmann
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Diana Marin Correa
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Silvia Cellone Trevelin
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Qi Peng
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Elena Crespo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Mauro Corrado
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Juan-José Lozano
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph Stelzmannstrasse 26, 50931, Cologne, Germany.
| | - Erika L Pearce
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Calle Rossello 153 Bajos, O8036, Barcelona, Spain.
| | - Elena Perpinan
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Anna Zoccarato
- Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany.
| | - Leonard Siew
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Joy Edwards-Hicks
- Centre for Liver and Gastroenterology Research and Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
| | - Reenam Khan
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Nguyet-Thin Luu
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Mark R Thursz
- Institute of Liver Sciences, King's College Hospital NHS Foundation Trust, London, SE5 9NU, United Kingdom.
| | - Philip N Newsome
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Marc Martinez-Llordella
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Naina Shah
- James Black Centre, Department of Cardiovascular sciences, British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, SE5 9NU, United Kingdom.
| | - Robert I Lechler
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Ajay M Shah
- Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany.
| | - Alberto Sanchez-Fueyo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Niloufar Safinia
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
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3
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Huang CC, Hsueh YW, Chang CW, Hsu HC, Yang TC, Lin WC, Chang HM. Establishment of the fetal-maternal interface: developmental events in human implantation and placentation. Front Cell Dev Biol 2023; 11:1200330. [PMID: 37266451 PMCID: PMC10230101 DOI: 10.3389/fcell.2023.1200330] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/09/2023] [Indexed: 06/03/2023] Open
Abstract
Early pregnancy is a complex and well-orchestrated differentiation process that involves all the cellular elements of the fetal-maternal interface. Aberrant trophoblast-decidual interactions can lead to miscarriage and disorders that occur later in pregnancy, including preeclampsia, intrauterine fetal growth restriction, and preterm labor. A great deal of research on the regulation of implantation and placentation has been performed in a wide range of species. However, there is significant species variation regarding trophoblast differentiation as well as decidual-specific gene expression and regulation. Most of the relevant information has been obtained from studies using mouse models. A comprehensive understanding of the physiology and pathology of human implantation and placentation has only recently been obtained because of emerging advanced technologies. With the derivation of human trophoblast stem cells, 3D-organoid cultures, and single-cell analyses of differentiated cells, cell type-specific transcript profiles and functions were generated, and each exhibited a unique signature. Additionally, through integrative transcriptomic information, researchers can uncover the cellular dysfunction of embryonic and placental cells in peri-implantation embryos and the early pathological placenta. In fact, the clinical utility of fetal-maternal cellular trafficking has been applied for the noninvasive prenatal diagnosis of aneuploidies and the prediction of pregnancy complications. Furthermore, recent studies have proposed a viable path toward the development of therapeutic strategies targeting placenta-enriched molecules for placental dysfunction and diseases.
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4
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Lianos EA, Detsika MG. Metalloporphyrins as Tools for Deciphering the Role of Heme Oxygenase in Renal Immune Injury. Int J Mol Sci 2023; 24:6815. [PMID: 37047787 PMCID: PMC10095062 DOI: 10.3390/ijms24076815] [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: 03/14/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023] Open
Abstract
Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current treatments to preserve renal function continue to be based mainly on systemic immunosuppression. Small molecules, naturally occurring biologic agents, show considerable promise in acting as disease modifiers and may provide novel therapeutic leads. Certain naturally occurring or synthetic Metalloporphyrins (Mps) can act as disease modifiers by increasing heme oxygenase (HO) enzymatic activity and/or synthesis of the inducible HO isoform (HO-1). Depending on the metal moiety of the Mp employed, these effects may occur in tandem or can be discordant (increased HO-1 synthesis but inhibition of enzyme activity). This review discusses effects of Mps, with varying redox-active transitional metals and cyclic porphyrin cores, on mechanisms underlying pathogenesis and outcomes of renal immune injury.
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Affiliation(s)
- Elias A. Lianos
- Veterans Affairs Medical Center and Virginia Tech, Carilion School of Medicine, Salem, VA 24153, USA
| | - Maria G. Detsika
- GP Livanos and M Simou Laboratories, Evangelismos Hospital, 1st Department of Critical Care Medicine & Pulmonary Services, National and Kapodistrian University of Athens, 10675 Athens, Greece
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5
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Crump LS, Kines KT, Richer JK, Lyons TR. Breast cancers co-opt normal mechanisms of tolerance to promote immune evasion and metastasis. Am J Physiol Cell Physiol 2022; 323:C1475-C1495. [PMID: 36189970 PMCID: PMC9662806 DOI: 10.1152/ajpcell.00189.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/22/2022]
Abstract
Normal developmental processes, such as those seen during embryonic development and postpartum mammary gland involution, can be reactivated by cancer cells to promote immune suppression, tumor growth, and metastatic spread. In mammalian embryos, paternal-derived antigens are at risk of being recognized as foreign by the maternal immune system. Suppression of the maternal immune response toward the fetus, which is mediated in part by the trophoblast, is critical to ensure embryonic survival and development. The postpartum mammary microenvironment also exhibits immunosuppressive mechanisms accompanying the massive cell death and tissue remodeling that occurs during mammary gland involution. These normal immunosuppressive mechanisms are paralleled during malignant transformation, where tumors can develop neoantigens that may be recognized as foreign by the immune system. To circumvent this, tumors can dedifferentiate and co-opt immune-suppressive mechanisms normally utilized during fetal tolerance and postpartum mammary involution. In this review, we discuss those similarities and how they can inform our understanding of cancer progression and metastasis.
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Affiliation(s)
- Lyndsey S Crump
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kelsey T Kines
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
| | - Traci R Lyons
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
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6
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Silva RCMC, Vasconcelos LR, Travassos LH. The different facets of heme-oxygenase 1 in innate and adaptive immunity. Cell Biochem Biophys 2022; 80:609-631. [PMID: 36018440 DOI: 10.1007/s12013-022-01087-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 07/20/2022] [Indexed: 11/26/2022]
Abstract
Heme oxygenase (HO) enzymes are responsible for the main oxidative step in heme degradation, generating equimolar amounts of free iron, biliverdin and carbon monoxide. HO-1 is induced as a crucial stress response protein, playing protective roles in physiologic and pathological conditions, due to its antioxidant, anti-apoptotic and anti-inflammatory effects. The mechanisms behind HO-1-mediated protection are being explored by different studies, affecting cell fate through multiple ways, such as reduction in intracellular levels of heme and ROS, transcriptional regulation, and through its byproducts generation. In this review we focus on the interplay between HO-1 and immune-related signaling pathways, which culminate in the activation of transcription factors important in immune responses and inflammation. We also discuss the dual interaction of HO-1 and inflammatory mediators that govern resolution and tissue damage. We highlight the dichotomy of HO-1 in innate and adaptive immune cells development and activation in different disease contexts. Finally, we address different known anti-inflammatory pharmaceuticals that are now being described to modulate HO-1, and the possible contribution of HO-1 in their anti-inflammatory effects.
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Affiliation(s)
- Rafael Cardoso Maciel Costa Silva
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Luiz Ricardo Vasconcelos
- Cellular Signaling and Cytoskeletal Function Laboratory, The Francis Crick Institute, London, UK
| | - Leonardo Holanda Travassos
- Laboratory of Immunoreceptors and Signaling, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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7
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Role of Butylphthalide in Immunity and Inflammation: Butylphthalide May Be a Potential Therapy for Anti-Inflammation and Immunoregulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7232457. [PMID: 35422893 PMCID: PMC9005281 DOI: 10.1155/2022/7232457] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 03/14/2022] [Indexed: 12/14/2022]
Abstract
Inflammation and immunity play an essential role in disease pathogenesis. 3-N-Butylphthalide (NBP), a group of compounds extracted from seeds of Apium graveolens (Chinese celery), has been demonstrated as an efficient and effective therapy for ischemic stroke. The amount of research on NBP protective effect is increasing at pace, such as microcircular reconstruction, alleviating inflammation, ameliorating brain edema and blood-brain barrier (BBB) damage, mitochondrial function protection, antiplatelet aggregation, antithrombosis, decreasing oxidative damage, and reducing neural cell apoptosis. There has been increasing research emphasizing the association between NBP and immunity and inflammation in the past few years. Hence, it is aimed at reviewing the related literature and summarizing the underlying anti-inflammatory and immunoregulatory function of NBP in various disorders.
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8
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Sarkesh A, Sorkhabi AD, Ahmadi H, Abdolmohammadi-Vahid S, Parhizkar F, Yousefi M, Aghebati-Maleki L. Allogeneic lymphocytes immunotherapy in female infertility: Lessons learned and the road ahead. Life Sci 2022; 299:120503. [PMID: 35381221 DOI: 10.1016/j.lfs.2022.120503] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/12/2022] [Accepted: 03/22/2022] [Indexed: 02/07/2023]
Abstract
The endometrium is an essential tissue in the normal immunologic dialogue between the mother and the conceptus, which is necessary for the proper establishment and maintenance of a successful pregnancy. It's become evident that the maternal immune system plays a key role in the normal pregnancy's initiation, maintenance, and termination. In this perspective, the immune system contributes to regulating all stages of pregnancy, thus immunological dysregulation is thought to be one of the major etiologies of implantation failures. Many researchers believe that immune therapies are useful tactics for improving the live births rate in certain situations. Lymphocyte immunotherapy (LIT) is an active form of immunotherapy that, when used on the relevant subgroups of patients, has been shown in multiple trials to dramatically enhance maternal immunological balance and pregnancy outcome. The primary goal of LIT is to regulate the immune system in order to create a favorable tolerogenic immune milieu and tolerance for embryo implantation. However, there are a plethora of influential factors influencing its therapeutic benefits that merit to be addressed. The objective of our study is to discuss the mechanisms and challenges of allogeneic LIT.
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Affiliation(s)
- Aila Sarkesh
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Daei Sorkhabi
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Ahmadi
- Department of Medical Biology and Central Electron Microscope Laboratory, Medical School, Pécs University, Pécs, Hungary
| | | | - Forough Parhizkar
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Science, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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9
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Immune Regulation of Heme Oxygenase-1 in Allergic Airway Inflammation. Antioxidants (Basel) 2022; 11:antiox11030465. [PMID: 35326116 PMCID: PMC8944570 DOI: 10.3390/antiox11030465] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/09/2022] [Accepted: 02/23/2022] [Indexed: 11/17/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is not only a rate-limiting enzyme in heme metabolism but is also regarded as a protective protein with an immunoregulation role in asthmatic airway inflammation. HO-1 exerts an anti-inflammation role in different stages of airway inflammation via regulating various immune cells, such as dendritic cells, mast cells, basophils, T cells, and macrophages. In addition, the immunoregulation role of HO-1 may differ according to subcellular locations.
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10
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Campbell NK, Fitzgerald HK, Dunne A. Regulation of inflammation by the antioxidant haem oxygenase 1. Nat Rev Immunol 2021; 21:411-425. [PMID: 33514947 DOI: 10.1038/s41577-020-00491-x] [Citation(s) in RCA: 250] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 01/30/2023]
Abstract
Haem oxygenase 1 (HO-1), an inducible enzyme responsible for the breakdown of haem, is primarily considered an antioxidant, and has long been overlooked by immunologists. However, research over the past two decades in particular has demonstrated that HO-1 also exhibits numerous anti-inflammatory properties. These emerging immunomodulatory functions have made HO-1 an appealing target for treatment of diseases characterized by high levels of chronic inflammation. In this Review, we present an introduction to HO-1 for immunologists, including an overview of its roles in iron metabolism and antioxidant defence, and the factors which regulate its expression. We discuss the impact of HO-1 induction in specific immune cell populations and provide new insights into the immunomodulation that accompanies haem catabolism, including its relationship to immunometabolism. Furthermore, we highlight the therapeutic potential of HO-1 induction to treat chronic inflammatory and autoimmune diseases, and the issues faced when trying to translate such therapies to the clinic. Finally, we examine a number of alternative, safer strategies that are under investigation to harness the therapeutic potential of HO-1, including the use of phytochemicals, novel HO-1 inducers and carbon monoxide-based therapies.
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Affiliation(s)
- Nicole K Campbell
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. .,Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. .,Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
| | - Hannah K Fitzgerald
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Aisling Dunne
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,School of Medicine, Trinity College Dublin, Dublin, Ireland
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11
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Szade A, Szade K, Mahdi M, Józkowicz A. The role of heme oxygenase-1 in hematopoietic system and its microenvironment. Cell Mol Life Sci 2021; 78:4639-4651. [PMID: 33787980 PMCID: PMC8195762 DOI: 10.1007/s00018-021-03803-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 02/09/2021] [Accepted: 02/24/2021] [Indexed: 12/22/2022]
Abstract
Hematopoietic system transports all necessary nutrients to the whole organism and provides the immunological protection. Blood cells have high turnover, therefore, this system must be dynamically controlled and must have broad regeneration potential. In this review, we summarize how this complex system is regulated by the heme oxygenase-1 (HO-1)-an enzyme, which degrades heme to biliverdin, ferrous ion and carbon monoxide. First, we discuss how HO-1 influences hematopoietic stem cells (HSC) self-renewal, aging and differentiation. We also describe a critical role of HO-1 in endothelial cells and mesenchymal stromal cells that constitute the specialized bone marrow niche of HSC. We further discuss the molecular and cellular mechanisms by which HO-1 modulates innate and adaptive immune responses. Finally, we highlight how modulation of HO-1 activity regulates the mobilization of bone marrow hematopoietic cells to peripheral blood. We critically discuss the issue of metalloporphyrins, commonly used pharmacological modulators of HO-1 activity, and raise the issue of their important HO-1-independent activities.
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Affiliation(s)
- Agata Szade
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.
| | - Krzysztof Szade
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Mahdi Mahdi
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Alicja Józkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
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12
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Luu Hoang KN, Anstee JE, Arnold JN. The Diverse Roles of Heme Oxygenase-1 in Tumor Progression. Front Immunol 2021; 12:658315. [PMID: 33868304 PMCID: PMC8044534 DOI: 10.3389/fimmu.2021.658315] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/15/2021] [Indexed: 12/16/2022] Open
Abstract
Heme oxygenase-1 (HO-1) is an inducible intracellular enzyme that is expressed in response to a variety of stimuli to degrade heme, which generates the biologically active catabolites carbon monoxide (CO), biliverdin and ferrous iron (Fe2+). HO-1 is expressed across a range of cancers and has been demonstrated to promote tumor progression through a variety of mechanisms. HO-1 can be expressed in a variety of cells within the tumor microenvironment (TME), including both the malignant tumor cells as well as stromal cell populations such as macrophages, dendritic cells and regulatory T-cells. Intrinsically to the cell, HO-1 activity provides antioxidant, anti-apoptotic and cytoprotective effects via its catabolites as well as clearing toxic intracellular heme. However, the catabolites of heme degradation can also diffuse outside of the cell to extrinsically modulate the wider TME, influencing cellular functionality and biological processes which promote tumor progression, such as facilitating angiogenesis and metastasis, as well as promoting anti-inflammation and immune suppression. Pharmacological inhibition of HO-1 has been demonstrated to be a promising therapeutic approach to promote anti-tumor immune responses and inhibit metastasis. However, these biological functions might be context, TME and cell type-dependent as there is also conflicting reports for HO-1 activity facilitating anti-tumoral processes. This review will consider our current understanding of the role of HO-1 in cancer progression and as a therapeutic target in cancer.
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Affiliation(s)
- Kim Ngan Luu Hoang
- Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Joanne E Anstee
- Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - James N Arnold
- Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
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13
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Reprograming of Tumor-Associated Macrophages in Breast Tumor-Bearing Mice under Chemotherapy by Targeting Heme Oxygenase-1. Antioxidants (Basel) 2021; 10:antiox10030470. [PMID: 33809707 PMCID: PMC8002331 DOI: 10.3390/antiox10030470] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor-associated macrophages (TAMs) represent one of the most abundant components of the tumor microenvironment and play important roles in tumor development and progression. TAMs display plasticity and functional heterogeneity as reflected by distinct phenotypic subsets. TAMs with an M1 phenotype have proinflammatory and anti-tumoral properties whereas M2-like TAMs exert anti-inflammatory and pro-tumoral functions. Tumor cell debris generated during chemotherapy can stimulate primary tumor growth and recurrence. According to our previous study, phagocytic engulfment of breast tumor cell debris by TAMs attenuated chemotherapeutic efficacy through the upregulation of heme oxygenase-1 (HO-1). To verify the impact of HO-1 upregulation on the profile of macrophage polarization during cytotoxic therapy, we utilized a syngeneic murine breast cancer (4T1) model in which tumor bearing mice were treated with paclitaxel (PTX). PTX treatment markedly downregulated the surface expression of the M1 marker CD86 in infiltrated TAMs. Notably, there were significantly more cytotoxic CD8+ T cells in tumors of mice treated with PTX plus the HO-1 inhibitor, zinc protophorphyrin IX (ZnPP) than in mice treated with PTX alone. Interestingly, the tumor-inhibiting efficacy of PTX and ZnPP co-treatment was abrogated when macrophages were depleted by clodronate liposomes. Macrophage depletion also decreased the intratumoral CD8+ T cell population and downregulated the expression of Cxcl9 and Cxcl10. The expression of the M1 phenotype marker, CD86 was higher in mice injected with PTX plus ZnPP than that in mice treated with PTX alone. Conversely, the PTX-induced upregulation of the M2 marker gene, Il10 in CD11b+ myeloid cells from 4T1 tumor-bearing mice treated was dramatically reduced by the administration of the HO-1 inhibitor. Genetic ablation of HO-1 abolished the inhibitory effect of 4T1 tumor cell debris on expression of M1 marker genes, Tnf and Il12b, in LPS-stimulated BMDMs. HO-1-deficient BMDMs exposed to tumor cell debris also exhibited a diminished expression of the M2 macrophage marker, CD206. These findings, taken all together, provide strong evidence that HO-1 plays a pivotal role in the transition of tumor-inhibiting M1-like TAMs to tumor-promoting M2-like ones during chemotherapy.
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14
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Was H, Cichon T, Smolarczyk R, Lackowska B, Mazur-Bialy A, Mazur M, Szade A, Dominik P, Mazan M, Kotlinowski J, Zebzda A, Kusienicka A, Kieda C, Dulak J, Jozkowicz A. Effect of Heme Oxygenase-1 on Melanoma Development in Mice-Role of Tumor-Infiltrating Immune Cells. Antioxidants (Basel) 2020; 9:E1223. [PMID: 33287312 PMCID: PMC7761646 DOI: 10.3390/antiox9121223] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Heme oxygenase-1 (HO-1) is a cytoprotective, proangiogenic and anti-inflammatory enzyme that is often upregulated in tumors. Overexpression of HO-1 in melanoma cells leads to enhanced tumor growth, augmented angiogenesis and resistance to anticancer treatment. The effect of HO-1 in host cells on tumor development is, however, hardly known. METHODS AND RESULTS To clarify the effect of HO-1 expression in host cells on melanoma progression, C57BL/6xFvB mice of different HO-1 genotypes, HO-1+/+, HO-1+/-, and HO-1-/-, were injected with the syngeneic wild-type murine melanoma B16(F10) cell line. Lack of HO-1 in host cells did not significantly influence the host survival. Nevertheless, in comparison to the wild-type counterparts, the HO-1+/- and HO-1-/- males formed bigger tumors, and more numerous lung nodules; in addition, more of them had liver and spleen micrometastases. Females of all genotypes developed at least 10 times smaller tumors than males. Of importance, the growth of primary and secondary tumors was completely blocked in HO-1+/+ females. This was related to the increased infiltration of leukocytes (mainly lymphocytes T) in primary tumors. CONCLUSIONS Although HO-1 overexpression in melanoma cells can enhance tumor progression in mice, its presence in host cells, including immune cells, can reduce growth and metastasis of melanoma.
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Affiliation(s)
- Halina Was
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland;
| | - Tomasz Cichon
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland; (T.C.); (R.S.)
| | - Ryszard Smolarczyk
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland; (T.C.); (R.S.)
| | - Bozena Lackowska
- Department of Pathology, Oncology Center, 31-115 Krakow, Poland;
| | - Agnieszka Mazur-Bialy
- Department of Ergonomics and Exercise Physiology, Faculty of Health Science, Jagiellonian University Medical College, 31-126 Krakow, Poland;
| | - Magdalena Mazur
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Agata Szade
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Pawel Dominik
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Milena Mazan
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Jerzy Kotlinowski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Anna Zebzda
- Transplantation Centre, Jagiellonian University, 30-663 Krakow, Poland;
| | - Anna Kusienicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, 04-141 Warsaw, Poland;
| | - Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
| | - Alicja Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland; (M.M.); (A.S.); (P.D.); (M.M.); (J.K.); (A.K.); (J.D.); (A.J.)
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15
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Calvani M, Dabraio A, Subbiani A, Buonvicino D, De Gregorio V, Ciullini Mannurita S, Pini A, Nardini P, Favre C, Filippi L. β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy. Front Immunol 2020; 11:2098. [PMID: 32983164 PMCID: PMC7492666 DOI: 10.3389/fimmu.2020.02098] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 08/03/2020] [Indexed: 12/14/2022] Open
Abstract
Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.
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Affiliation(s)
- Maura Calvani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Annalisa Dabraio
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | - Angela Subbiani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | | | - Veronica De Gregorio
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | - Sara Ciullini Mannurita
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Patrizia Nardini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudio Favre
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children's Hospital, Florence, Italy
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16
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Funes SC, Rios M, Fernández-Fierro A, Covián C, Bueno SM, Riedel CA, Mackern-Oberti JP, Kalergis AM. Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases. Front Immunol 2020; 11:1467. [PMID: 32849503 PMCID: PMC7396584 DOI: 10.3389/fimmu.2020.01467] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Heme oxygenase (HO) is the primary antioxidant enzyme involved in heme group degradation. A variety of stimuli triggers the expression of the inducible HO-1 isoform, which is modulated by its substrate and cellular stressors. A major anti-inflammatory role has been assigned to the HO-1 activity. Therefore, in recent years HO-1 induction has been employed as an approach to treating several disorders displaying some immune alterations components, such as exacerbated inflammation or self-reactivity. Many natural compounds have shown to be effective inductors of HO-1 without cytotoxic effects; among them, most are chemicals present in plants used as food, flavoring, and medicine. Here we discuss some naturally derived compounds involved in HO-1 induction, their impact in the immune response modulation, and the beneficial effect in diverse autoimmune disorders. We conclude that the use of some compounds from natural sources able to induce HO-1 is an attractive lifestyle toward promoting human health. This review opens a new outlook on the investigation of naturally derived HO-1 inducers, mainly concerning autoimmunity.
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Affiliation(s)
- Samanta C Funes
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Mariana Rios
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ayleen Fernández-Fierro
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Camila Covián
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia A Riedel
- Departamento de Ciencias Biológicas, Millenium Institute on Immunolgy and Immunotherapy, Facultad Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
| | - Juan Pablo Mackern-Oberti
- Instituto de Medicina y Biología Experimental de Cuyo, IMBECU CCT Mendoza- CONICET, Mendoza, Argentina.,Facultad de Ciencias Médicas, Instituto de Fisiología, Universidad Nacional de Cuyo, Mendoza, Argentina
| | - Alexis M Kalergis
- Departamento de Genética Molecular y Microbiología, Millenium Institute on Immunology and Immunotherapy, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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17
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Drescher HK, Schippers A, Rosenhain S, Gremse F, Bongiovanni L, de Bruin A, Eswaran S, Gallage SU, Pfister D, Szydlowska M, Heikenwalder M, Weiskirchen S, Wagner N, Trautwein C, Weiskirchen R, Kroy DC. L-Selectin/CD62L is a Key Driver of Non-Alcoholic Steatohepatitis in Mice and Men. Cells 2020; 9:cells9051106. [PMID: 32365632 PMCID: PMC7290433 DOI: 10.3390/cells9051106] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 04/20/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two mouse models of steatohepatitis. Hepatic expression of a soluble form of CD62L (sCD62L) was measured in patients with steatosis and NASH. Furthermore, CD62L−/− mice were fed with a methionine and choline deficient (MCD) diet for 4 weeks or with a high fat diet (HFD) for 24 weeks. Patients with NASH displayed increased serum levels of sCD62L. Hepatic CD62L expression was higher in patients with steatosis and increased dramatically in NASH patients. Interestingly, compared to wild type (WT) mice, MCD and HFD-treated CD62L−/− mice were protected from diet-induced steatohepatitis. This was reflected by less fat accumulation in hepatocytes and a dampened manifestation of the metabolic syndrome with an improved insulin resistance and decreased cholesterol and triglyceride levels. Consistent with ameliorated disease, CD62L−/− animals exhibited an enhanced hepatic infiltration of Treg cells and a strong activation of an anti-oxidative stress response. Those changes finally resulted in less fibrosis in CD62L−/− mice. Additionally, this effect could be reproduced in a therapeutic setting by administrating an anti-CD62L blocking antibody. CD62L expression in humans and mice correlates with disease activity of steatohepatitis. CD62L knockout and anti-CD62L-treated mice are protected from diet-induced steatohepatitis suggesting that CD62L is a promising target for therapeutic interventions in NASH.
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Affiliation(s)
- Hannah K. Drescher
- Department of Internal Medicine III, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (C.T.); (D.C.K.)
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Correspondence:
| | - Angela Schippers
- Department of Pediatrics, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (A.S.); (S.E.); (N.W.)
| | - Stefanie Rosenhain
- Institute for Experimental Molecular Imaging, University Hospital, RWTH Aachen University, 52074 Aachen, Germany; (S.R.); (F.G.)
| | - Felix Gremse
- Institute for Experimental Molecular Imaging, University Hospital, RWTH Aachen University, 52074 Aachen, Germany; (S.R.); (F.G.)
| | - Laura Bongiovanni
- Dutch Molecular Pathology Centre, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, The Netherlands; (L.B.); (A.d.B.)
| | - Alain de Bruin
- Dutch Molecular Pathology Centre, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, The Netherlands; (L.B.); (A.d.B.)
| | - Sreepradha Eswaran
- Department of Pediatrics, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (A.S.); (S.E.); (N.W.)
| | - Suchira U. Gallage
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), 69120 Heidelberg, Germany; (S.U.G.); (D.P.); (M.S.); (M.H.)
| | - Dominik Pfister
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), 69120 Heidelberg, Germany; (S.U.G.); (D.P.); (M.S.); (M.H.)
| | - Marta Szydlowska
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), 69120 Heidelberg, Germany; (S.U.G.); (D.P.); (M.S.); (M.H.)
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), 69120 Heidelberg, Germany; (S.U.G.); (D.P.); (M.S.); (M.H.)
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen University, 52074 Aachen, Germany; (S.W.); (R.W.)
| | - Norbert Wagner
- Department of Pediatrics, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (A.S.); (S.E.); (N.W.)
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (C.T.); (D.C.K.)
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital, RWTH Aachen University, 52074 Aachen, Germany; (S.W.); (R.W.)
| | - Daniela C. Kroy
- Department of Internal Medicine III, University Hospital, RWTH Aachen, 52074 Aachen, Germany; (C.T.); (D.C.K.)
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Siddiq M, Wang F, Xiao M, Lin XJ, Fatima N, Iqbal S, Iqbal U, Piao XH, Liu L. Inhibition of lipopolysaccharide-induced inflammation via the protective role of T regulatory cells in the fetal liver in a late-pregnancy preterm mouse model. Clinics (Sao Paulo) 2020; 75:e1665. [PMID: 33206750 PMCID: PMC7603294 DOI: 10.6061/clinics/2020/e1665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 03/26/2020] [Indexed: 12/05/2022] Open
Abstract
OBJECTIVES This study intended to explore the effect of T regulatory cells (Tregs) in the perinatal liver against LPS-induced inflammation in a preterm birth mouse model. Moreover, the role of adoptive Tregs on the inflammatory response induced by LPS was also studied. METHODS Female BALB/C mice were injected intraperitoneally (IP) with LPS dissolved in normal saline solution at a dose of 50 µg/kg. Spleens from pregnant mice were used to obtain Tregs. The expression of Forkhead family transcription factor-3 (Foxp3), Interleukin-6 (IL-6), Toll-like receptor-4 (TLR-4), and Heme oxygenase-1 (HO-1) were assessed from fetal liver tissues by polymerase chain reaction and western blotting. RESULTS LPS administered to mice induced an inflammatory response in the perinatal liver, and this inflammatory response was negatively regulated by Tregs in the experimental group. Maternal-fetal tolerance was maintained by Tregs. Transmission of Tregs was estimated in different experimental groups based on the mRNA expression of TLR-4, IL-6, HO-1, and Foxp3. CONCLUSIONS After analysis of the experimental data, it was determined that Tregs exhibited regulatory potential against LPS-induced inflammatory response. Further, it was concluded that the transmission of Tregs improved the mother's immune tolerance against LPS-induced inflammation in the fetal liver.
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Affiliation(s)
- Muhammad Siddiq
- Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, China
| | - Fan Wang
- Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, China
| | - Mi Xiao
- Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, China
| | - Xiao Jie Lin
- Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, China
| | - Nazira Fatima
- Department of Biotechnology, Mirpur University of Science & Technology Pakistan, Pakistan and Laboratory Animal Center Xian Jiaotong University Health Science Centre, Xian Shaanxi, China
| | - Sara Iqbal
- Akhtar Saeed Medical & Dental College, Akhtar Saeed Trust Hospital & Farooq Hospital Lahore, Akhtar Saeed Medical & Dental CollegeAkhtar Saeed Trust Hospital & Farooq Hospital LahorePakistanPakistan
| | - Umar Iqbal
- Akhtar Saeed Medical & Dental College, Akhtar Saeed Trust Hospital & Farooq Hospital Lahore, Akhtar Saeed Medical & Dental CollegeAkhtar Saeed Trust Hospital & Farooq Hospital LahorePakistanPakistan
| | - Xian-Hua Piao
- The Division of Newborn Medicine, Boston Children’s Hospital of Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Li Liu
- Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, China
- *Corresponding authors. E-mail:
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19
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Cuitino L, Obreque J, Gajardo-Meneses P, Villarroel A, Crisóstomo N, San Francisco IF, Valenzuela RA, Méndez GP, Llanos C. Heme-Oxygenase-1 Is Decreased in Circulating Monocytes and Is Associated With Impaired Phagocytosis and ROS Production in Lupus Nephritis. Front Immunol 2019; 10:2868. [PMID: 31921135 PMCID: PMC6923251 DOI: 10.3389/fimmu.2019.02868] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 11/22/2019] [Indexed: 12/18/2022] Open
Abstract
Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus (SLE). Based on studies showing the potential role of heme oxygenase-1 (HO-1), an enzyme that catalyzes the degradation of heme and has anti-inflammatory properties in SLE development, we decided to explore HO-1 in LN. Accordingly, we evaluated HO-1 levels and function in circulating and infiltrating monocytes and neutrophils of LN patients. HO-1 levels were assessed in peripheral monocytes of LN patients and controls by flow cytometry and immunofluorescence microscopy. Phagocytosis and the production of reactive oxygen species (ROS) were evaluated to determine the effect of HO-1 in monocyte function. In addition, renal biopsies with proliferative LN were used to identify HO-1 in infiltrating cells and renal tissue by immunofluorescence and immunohistochemistry. Biopsies of healthy controls (HC) and patients who underwent nephrectomy were included as controls. Circulating pro-inflammatory monocytes and activated neutrophils were increased in LN patients. HO-1 levels were decreased in all subsets of monocytes and in activated neutrophils. LN monocytes showed increased phagocytosis and higher production of ROS than those of HC. When HO-1 was induced, phagocytosis and ROS levels became similar to those of HC. HO-1 was mostly expressed in renal tubular epithelial cells (RTEC). Renal tissue of LN patients showed lower levels of HO-1 than HC, whereas infiltrating immune cells of LN showed lower levels of HO-1 than biopsies of patients who had renal surgery. HO-1 is decreased in circulating monocytes and activated neutrophils of LN patients. HO-1 levels modulate the phagocytosis of LN monocytes and ROS production. HO-1 expression in RTEC might be an attempt of self-protection from inflammation.
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Affiliation(s)
- Loreto Cuitino
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Javiera Obreque
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Patricia Gajardo-Meneses
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandra Villarroel
- Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Natalia Crisóstomo
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ignacio F San Francisco
- Departamento de Urología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo A Valenzuela
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Gonzalo P Méndez
- Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Llanos
- Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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20
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Drummond GS, Baum J, Greenberg M, Lewis D, Abraham NG. HO-1 overexpression and underexpression: Clinical implications. Arch Biochem Biophys 2019; 673:108073. [PMID: 31425676 DOI: 10.1016/j.abb.2019.108073] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/23/2019] [Accepted: 08/10/2019] [Indexed: 12/11/2022]
Abstract
In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.
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Affiliation(s)
- George S Drummond
- Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Jeffrey Baum
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Menachem Greenberg
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - David Lewis
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY, 10595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, 25701, USA.
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21
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Optimizing regulatory T cells for therapeutic application in human organ transplantation. Curr Opin Organ Transplant 2018; 23:516-523. [DOI: 10.1097/mot.0000000000000561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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22
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Fagone P, Mazzon E, Bramanti P, Bendtzen K, Nicoletti F. Gasotransmitters and the immune system: Mode of action and novel therapeutic targets. Eur J Pharmacol 2018; 834:92-102. [PMID: 30016662 DOI: 10.1016/j.ejphar.2018.07.026] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 06/29/2018] [Accepted: 07/13/2018] [Indexed: 12/12/2022]
Abstract
Gasotransmitters are a group of gaseous molecules, with pleiotropic biological functions. These molecules include nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). Abnormal production and metabolism of these molecules have been observed in several pathological conditions. The understanding of the role of gasotransmitters in the immune system has grown significantly in the past years, and independent studies have shed light on the effect of exogenous and endogenous gasotransmitters on immune responses. Moreover, encouraging results come from the efficacy of NO-, CO- and H2S -donors in preclinical animal models of autoimmune, acute and chronic inflammatory diseases. To date, data on the influence of gasotransmitters in immunity and immunopathology are often scattered and partial, and the scarcity of clinical trials using NO-, CO- and H2S -donors, reveals that more effort is warranted. This review focuses on the role of gasotransmitters in the immune system and covers the evidences on the possible use of gasotransmitters for the treatment of inflammatory conditions.
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Affiliation(s)
- Paolo Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Placido Bramanti
- IRCCS Centro Neurolesi Bonino Pulejo, Stada Statale 113, C.da Casazza, 98124 Messina, Italy
| | - Klaus Bendtzen
- Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
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23
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Kofod L, Lindhard A, Hviid TVF. Implications of uterine NK cells and regulatory T cells in the endometrium of infertile women. Hum Immunol 2018; 79:693-701. [PMID: 29990511 DOI: 10.1016/j.humimm.2018.07.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 07/02/2018] [Accepted: 07/06/2018] [Indexed: 02/03/2023]
Abstract
A range of studies have shown that the complex process of implantation and an establishment of a pregnancy also involves immune factors. Disturbances in these underlying immune mechanisms might lead to implantation and pregnancy failure and may be involved in the pathogenesis of unexplained infertility. Several studies have reported that imbalances in uterine NK (uNK) cell abundance are associated with infertility; however, controversies exist. An increased amount of CD56+ uNK cells along with a decrease in CD16+ uNK cells have been associated with normal fertility in some studies. Very few studies of FoxP3+ regulatory T cells (Tregs) in the pre-implantation endometrium have been performed. Results are sparse and controversial, studies reporting both increased and decreased numbers of Tregs, respectively, in women suffering from infertility. In conclusion, studies imply that uNK cells, Tregs and HLA-G carry pivotal roles regarding the establishment of a healthy pregnancy, and that abnormal immune mechanisms involving these parameters may be associated with infertility. However, more research in early phases of the reproductive cycle, such as investigating the conditions in the endometrium before implantation, is needed to further clarify the underlying mechanisms.
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Affiliation(s)
- Louise Kofod
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Research Consortium ZUH, Department of Clinical Biochemistry, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Anette Lindhard
- The Fertility Clinic, The ReproHealth Research Consortium ZUH, Department of Gynaecology and Obstetrics, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Thomas Vauvert F Hviid
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), The ReproHealth Research Consortium ZUH, Department of Clinical Biochemistry, Zealand University Hospital, and Department of Clinical Medicine, University of Copenhagen, Denmark.
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24
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Marek-Trzonkowska N, Piekarska K, Filipowicz N, Piotrowski A, Gucwa M, Vogt K, Sawitzki B, Siebert J, Trzonkowski P. Mild hypothermia provides Treg stability. Sci Rep 2017; 7:11915. [PMID: 28931834 PMCID: PMC5607276 DOI: 10.1038/s41598-017-10151-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 08/04/2017] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) play crucial role in maintenance of peripheral tolerance. Recent clinical trials confirmed safety and efficacy of Treg treatment of deleterious immune responses. However, Tregs lose their characteristic phenotype and suppressive potential during expansion ex vivo. Therefore, multiple research teams have been studding Treg biology in aim to improve their stability in vitro. In the current paper, we demonstrate that mild hypothermia of 33 °C induces robust proliferation of Tregs, preserves expression of FoxP3, CD25 and Helios, and prevents TSDR methylation during culture in vitro. Tregs expanded at 33 °C have stronger immunosuppressive potential and remarkably anti-inflammatory phenotype demonstrated by the whole transcriptome sequencing. These observations shed new light on impact of temperature on regulation of immune response. We show that just a simple change in temperature can preserve Treg stability, function and accelerate their proliferation, responding to unanswered question- how to preserve Treg stability in vitro.
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Affiliation(s)
- Natalia Marek-Trzonkowska
- Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, ul. Dębinki 2, 80-210, Gdańsk, Poland.
| | - Karolina Piekarska
- Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, ul. Dębinki 2, 80-210, Gdańsk, Poland
| | - Natalia Filipowicz
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland
| | - Arkadiusz Piotrowski
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland
| | - Magdalena Gucwa
- Department of Biology and Pharmaceutical Botany, Medical University of Gdańsk, al. Gen. J. Hallera 107, 80-416, Gdańsk, Poland
| | - Katrin Vogt
- Institute for Medical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Augustenburgerplatz 1, 13353, Berlin, Germany
| | - Birgit Sawitzki
- Institute for Medical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Augustenburgerplatz 1, 13353, Berlin, Germany
| | - Janusz Siebert
- Department of Family Medicine, Medical University of Gdańsk, ul. Dębinki 2, 80-210, Gdańsk, Poland
| | - Piotr Trzonkowski
- Department of Clinical Immunology and Transplantology, Medical University of Gdańsk, ul. Dębinki 7, 80-210, Gdańsk, Poland
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25
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Drescher HK, Schippers A, Clahsen T, Sahin H, Noels H, Hornef M, Wagner N, Trautwein C, Streetz KL, Kroy DC. β 7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis. J Hepatol 2017; 66:1251-1264. [PMID: 28192190 DOI: 10.1016/j.jhep.2017.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 12/30/2016] [Accepted: 02/01/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β7-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. METHODS Constitutive β7-Integrin deficient (β7-/-) and MAdCAM-1 deficient (MAdCAM-1-/-) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. RESULTS β7-/- mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1-/- mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β7-/- mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β7-/- animals. In contrast, MAdCAM-1-/- mice showed an upregulation of the anti-oxidative stress response. β7-/- animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (TReg) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1-/- mice. Those changes finally resulted in earlier and stronger collagen accumulation in β7-/- mice, whereas MAdCAM-1-/- mice were protected from fibrosis initiation. CONCLUSIONS Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β7-Integrin unexpectedly exerts protective effects. β7-/- mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β7-Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis. LAY SUMMARY The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced non-alcoholic steatohepatitis (NASH). Loss of MAdCAM-1 has beneficial effects regarding the development of NASH - manifested by reduced hepatic oxidative stress and decreased inflammation. In contrast, β7-Integrin-deficiency results in increased steatohepatitis.
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Affiliation(s)
- Hannah K Drescher
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
| | - Angela Schippers
- Department of Pediatrics, University Hospital, RWTH Aachen, Germany
| | - Thomas Clahsen
- Department of Pediatrics, University Hospital, RWTH Aachen, Germany
| | - Hacer Sahin
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
| | - Heidi Noels
- Institute of Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
| | - Mathias Hornef
- Institute of Medical Microbiology, University Hospital, RWTH Aachen, Germany
| | - Norbert Wagner
- Department of Pediatrics, University Hospital, RWTH Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
| | - Konrad L Streetz
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany
| | - Daniela C Kroy
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Germany.
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26
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Nitti M, Piras S, Marinari UM, Moretta L, Pronzato MA, Furfaro AL. HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation. Antioxidants (Basel) 2017; 6:antiox6020029. [PMID: 28475131 PMCID: PMC5488009 DOI: 10.3390/antiox6020029] [Citation(s) in RCA: 167] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 04/26/2017] [Accepted: 04/29/2017] [Indexed: 02/07/2023] Open
Abstract
The upregulation of heme oxygenase-1 (HO-1) is one of the most important mechanisms of cell adaptation to stress. Indeed, the redox sensitive transcription factor Nrf2 is the pivotal regulator of HO-1 induction. Through the antioxidant, antiapoptotic, and antinflammatory properties of its metabolic products, HO-1 plays a key role in healthy cells in maintaining redox homeostasis and in preventing carcinogenesis. Nevertheless, several lines of evidence have highlighted the role of HO-1 in cancer progression and its expression correlates with tumor growth, aggressiveness, metastatic and angiogenetic potential, resistance to therapy, tumor escape, and poor prognosis, even though a tumor- and tissue-specific activity has been observed. In this review, we summarize the current literature regarding the pro-tumorigenic role of HO-1 dependent tumor progression as a promising target in anticancer strategy.
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Affiliation(s)
- Mariapaola Nitti
- Department of Experimental Medicine, University of Genoa, Via L. B. Alberti 2, Genoa 16132, Italy.
| | - Sabrina Piras
- Department of Experimental Medicine, University of Genoa, Via L. B. Alberti 2, Genoa 16132, Italy.
| | - Umberto M Marinari
- Department of Experimental Medicine, University of Genoa, Via L. B. Alberti 2, Genoa 16132, Italy.
| | - Lorenzo Moretta
- Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, Rome 00165, Italy.
| | - Maria A Pronzato
- Department of Experimental Medicine, University of Genoa, Via L. B. Alberti 2, Genoa 16132, Italy.
| | - Anna Lisa Furfaro
- Giannina Gaslini Institute, IRCCS, Via Gerolamo Gaslini 5, Genoa 16147, Italy.
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27
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Chebotareva N, Bobkova I, Shilov E. Heat shock proteins and kidney disease: perspectives of HSP therapy. Cell Stress Chaperones 2017; 22:319-343. [PMID: 28409327 PMCID: PMC5425374 DOI: 10.1007/s12192-017-0790-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 02/11/2017] [Accepted: 03/20/2017] [Indexed: 12/11/2022] Open
Abstract
Heat shock proteins (HSPs) mediate a diverse range of cellular functions, prominently including folding and regulatory processes of cellular repair. A major property of these remarkable proteins, dependent on intracellular or extracellular location, is their capacity for immunoregulation that optimizes immune activity while avoiding hyperactivated inflammation. In this review, recent investigations are described, which examine roles of HSPs in protection of kidney tissue from various traumatic influences and demonstrate their potential for clinical management of nephritic disease. The HSP70 class is particularly attractive in this respect due to its multiple protective effects. The review also summarizes current understanding of HSP bioactivity in the pathophysiology of various kidney diseases, including acute kidney injury, diabetic nephropathy, chronic glomerulonephritis, and lupus nephritis-along with other promising strategies for their remediation, such as DNA vaccination.
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Affiliation(s)
- Natalia Chebotareva
- I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya st., Moscow, Russia, 119992.
| | - Irina Bobkova
- I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya st., Moscow, Russia, 119992
| | - Evgeniy Shilov
- I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya st., Moscow, Russia, 119992
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28
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Ghaebi M, Nouri M, Ghasemzadeh A, Farzadi L, Jadidi-Niaragh F, Ahmadi M, Yousefi M. Immune regulatory network in successful pregnancy and reproductive failures. Biomed Pharmacother 2017; 88:61-73. [PMID: 28095355 DOI: 10.1016/j.biopha.2017.01.016] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 12/27/2016] [Accepted: 01/02/2017] [Indexed: 12/23/2022] Open
Abstract
Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, γd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.
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Affiliation(s)
- Mahnaz Ghaebi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliyeh Ghasemzadeh
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Ahmadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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29
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Fierro N, Gonzalez-Aldaco K, Roman S, Panduro A. The Immune System and Viral Hepatitis. LIVER PATHOPHYSIOLOGY 2017:129-139. [DOI: 10.1016/b978-0-12-804274-8.00009-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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30
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Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, Morgan TE, Longo VD. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell 2016; 30:136-146. [PMID: 27411588 PMCID: PMC5388544 DOI: 10.1016/j.ccell.2016.06.005] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 01/30/2016] [Accepted: 06/10/2016] [Indexed: 12/22/2022]
Abstract
Immune-based interventions are promising strategies to achieve long-term cancer-free survival. Fasting was previously shown to differentially sensitize tumors to chemotherapy while protecting normal cells, including hematopoietic stem and immune cells, from its toxic side effects. Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity.
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Affiliation(s)
- Stefano Di Biase
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Changhan Lee
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Sebastian Brandhorst
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Brianna Manes
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Roberta Buono
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Chia-Wei Cheng
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Mafalda Cacciottolo
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Alejandro Martin-Montalvo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Min Wei
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Todd E. Morgan
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Valter D. Longo
- Longevity Institute, Leonard Davis School of Gerontology and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA
- IFOM, FIRC Institute of Molecular Oncology, Milano, Italy
- Correspondence to:
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31
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Zhong W, Di C, Lv J, Zhang Y, Lin X, Yuan Y, Lv J, Xia Z. Heme oxygenase-1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2-mediated allergic airway inflammation. Immunology 2016; 147:321-37. [PMID: 26879758 DOI: 10.1111/imm.12564] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 11/26/2015] [Accepted: 12/04/2015] [Indexed: 12/17/2022] Open
Abstract
The anti-inflammatory role of heme oxygenase-1 (HO-1) has been studied extensively in many disease models including asthma. Many cell types are anti-inflammatory targets of HO-1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO-1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen-induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up-regulation of HO-1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC-II and activation marker CD200R on basophils, blocked DQ-ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO-1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO-1. Furthermore, adoptive transfer of HO-1-modified basophils reduced ovalbumin-induced allergic airway inflammation. The above effects of HO-1 can be reversed by the HO-1 inhibitor Sn-protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO-1 may involve multiple immune cells. Collectively, our findings demonstrated that HO-1 exerted its anti-inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.
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Affiliation(s)
- Wenwei Zhong
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Paediatrics, Shanghai Children's Medical Centre affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Caixia Di
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajia Lv
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanjie Zhang
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoliang Lin
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufan Yuan
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Lv
- Department of Paediatrics, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenwei Xia
- Department of Paediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Galeotti C, Hegde P, Das M, Stephen-Victor E, Canale F, Muñoz M, Sharma VK, Dimitrov JD, Kaveri SV, Bayry J. Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin. Sci Rep 2016; 6:19592. [PMID: 26796539 PMCID: PMC4726216 DOI: 10.1038/srep19592] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects independent of HO-1 pathway.
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Affiliation(s)
- Caroline Galeotti
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France.,Department of Pediatric Rheumatology, National Referral Centre of Auto-inflammatory Diseases, CHU de Bicêtre, le Kremlin Bicêtre, F-94270, France
| | - Pushpa Hegde
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Mrinmoy Das
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Emmanuel Stephen-Victor
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Fernando Canale
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Marcos Muñoz
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Varun K Sharma
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France
| | - Jordan D Dimitrov
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France.,Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, F-75006, France
| | - Srini V Kaveri
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France.,Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, F-75006, France.,International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France - Indian council of Medical Research, India), National Institute of Immunohaematology, Mumbai, 400012, India
| | - Jagadeesh Bayry
- Institut National de la Santé et de la Recherche Médicale Unité 1138, Paris, F-75006, France.,Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, F-75006, France.,Centre de Recherche des Cordeliers, Equipe - Immunopathology and therapeutic immunointervention, Paris, F-75006, France.,Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, F-75006, France.,International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France - Indian council of Medical Research, India), National Institute of Immunohaematology, Mumbai, 400012, India
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Ryter SW, Choi AMK. Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 2016; 167:7-34. [PMID: 26166253 PMCID: PMC4857893 DOI: 10.1016/j.trsl.2015.06.011] [Citation(s) in RCA: 268] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 06/15/2015] [Accepted: 06/16/2015] [Indexed: 12/19/2022]
Abstract
The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV), the latter which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs through the generation of its biologically active end products, namely CO, BV and BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of proinflammatory or anti-inflammatory cytokines and mediators. HO-1 and CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural-inducing compounds and gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series or noncompetitive isoform-selective derivatives of imidazole-dioxolanes. The end products of HO activity, CO, BV and BR may be used therapeutically as pharmacologic treatments. CO may be applied by inhalation or through the use of CO-releasing molecules. This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia-reperfusion injury, and transplant rejection.
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Affiliation(s)
- Stefan W Ryter
- Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY.
| | - Augustine M K Choi
- Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY
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34
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Corral-Jara KF, Trujillo-Ochoa JL, Realpe M, Panduro A, Roman S, Fierro NA. Rethinking the immune properties of bilirubin in viral hepatitis: from bench to bedside. Clin Transl Immunology 2015; 4:e54. [PMID: 26719800 PMCID: PMC4685441 DOI: 10.1038/cti.2015.37] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 11/04/2015] [Accepted: 11/15/2015] [Indexed: 02/07/2023] Open
Abstract
Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.
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Affiliation(s)
- Karla F Corral-Jara
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Jorge L Trujillo-Ochoa
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Mauricio Realpe
- Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara , Guadalajara, Mexico
| | - Arturo Panduro
- Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
| | - Sonia Roman
- Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico ; Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico
| | - Nora A Fierro
- Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara 'Fray Antonio Alcalde' , Guadalajara, Mexico ; Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara , Guadalajara, Mexico
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Abraham NG, Junge JM, Drummond GS. Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome. Trends Pharmacol Sci 2015; 37:17-36. [PMID: 26515032 DOI: 10.1016/j.tips.2015.09.003] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/10/2015] [Accepted: 09/17/2015] [Indexed: 01/04/2023]
Abstract
The global epidemic of obesity continues unabated with sequelae of diabetes and metabolic syndrome. This review reflects the dramatic increase in research on the role of increased expression of heme oxygenase (HO)-1/HO-2, biliverdin reductase, and HO activity on vascular disease. The HO system engages with other systems to mitigate the deleterious effects of oxidative stress in obesity and cardiovascular disease (CVD). Recent reports indicate that HO-1/HO-2 protein expression and HO activity have several important roles in hemostasis and reactive oxygen species (ROS)-dependent perturbations associated with metabolic syndrome. HO-1 protects tissue during inflammatory stress in obesity through the degradation of pro-oxidant heme and the production of carbon monoxide (CO) and bilirubin, both of which have anti-inflammatory and anti-apoptotic properties. By contrast, repression of HO-1 is associated with increases of cellular heme and inflammatory conditions including hypertension, stroke, and atherosclerosis. HO-1 is a major focus in the development of potential therapeutic strategies to reverse the clinical complications of obesity and metabolic syndrome.
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Affiliation(s)
- Nader G Abraham
- Departments of Medicine and Pharmacology, New York Medical College, School of Medicine, Valhalla, NY 10595, USA; Marshall University, Joan C. Edwards School of Medicine, Huntington, WV 25701, USA.
| | - Joshua M Junge
- Departments of Medicine and Pharmacology, New York Medical College, School of Medicine, Valhalla, NY 10595, USA
| | - George S Drummond
- Departments of Medicine and Pharmacology, New York Medical College, School of Medicine, Valhalla, NY 10595, USA
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Mackern-Oberti JP, Obreque J, Méndez GP, Llanos C, Kalergis AM. Carbon monoxide inhibits T cell activation in target organs during systemic lupus erythematosus. Clin Exp Immunol 2015; 182:1-13. [PMID: 26095291 DOI: 10.1111/cei.12657] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2015] [Indexed: 01/15/2023] Open
Abstract
Systemic lupus erythematosus is characterized by the presence of circulating anti-nuclear antibodies (ANA) and systemic damage that includes nephritis, haematological manifestations and pulmonary compromise, among others. Although major progress has been made in elucidating the molecular mechanisms responsible for autoimmunity, current therapies for lupus have not improved considerably. Because the exposure of carbon monoxide (CO) has been shown to display beneficial immunoregulatory properties in different immune-mediated diseases, we investigated whether CO therapy improves lupus-related kidney injury in lupus mice. MRL-Fas(lpr) lupus mice were exposed to CO and disease progression was evaluated. ANA, leucocyte-infiltrating populations in spleen, kidney and lung and kidney lesions, were measured. CO therapy significantly decreased the frequency of activated B220(+) CD4(-) CD8(-) T cells in kidneys and lungs, as well as serum levels of ANA. Furthermore, we observed that CO therapy reduced kidney injury by decreasing proliferative glomerular damage and immune complexes deposition, decreased proinflammatory cytokine production and finally delayed the impairment of kidney function. CO exposure ameliorates kidney and lung leucocyte infiltration and delays kidney disease in MRL-Fas(lpr) lupus mice. Our data support the notion that CO could be explored as a potential new therapy for lupus nephritis.
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Affiliation(s)
- J P Mackern-Oberti
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Microbiología y Genética Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Institute of Medicine and Experimental Biology of Cuyo (IMBECU), Science and Technology Center (CCT) of Mendoza, National Council of Scientific and Technical Research (CONICET), Mendoza, Argentina
| | - J Obreque
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - G P Méndez
- Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - C Llanos
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - A M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Microbiología y Genética Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Inmunología Clínica y Reumatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Pontificia Universidad Católica de Chile, Santiago, Chile.,INSERM UMR 1064-Center for Research in Transplantation and Immunology, Nantes, France
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37
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ElEssawy B, Li XC. Type 1 diabetes and T regulatory cells. Pharmacol Res 2015; 98:22-30. [PMID: 25959211 DOI: 10.1016/j.phrs.2015.04.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 04/17/2015] [Accepted: 04/17/2015] [Indexed: 12/11/2022]
Abstract
T-regulatory cells (Tregs) play a fundamental role in the creation and maintenance of peripheral tolerance. Deficits in the numbers and/or function of Tregs may be an underlying cause of human autoimmune diseases including type 1 Diabetes Mellitus (T1D), whereas an over-abundance of Tregs can hinder immunity against cancer or pathogens. The importance of Tregs in the control of autoimmunity is well established in a variety of experimental animal models. In mice, manipulating the numbers and/or function of Tregs can decrease pathology in a wide range of contexts, including autoimmunity and it is widely assumed that similar approaches will be possible in humans. T1D, the most prevalent human autoimmune disease, has been a focus of interventions either through direct and indirect in vivo proliferations or through adoptive transfer of the in vitro generated antigen specific and non specific Treg. Some challenges still need to be addressed, including a more specific phenotype marker for Tregs; the reproducibility of satisfactory animal results in human and the reconcile of discrepancies between in vitro and in vivo studies. In this article, we will highlight the role of Tregs in autoimmune disease in general with a special focus on T1D, highlighting progress made and challenges ahead in developing Treg-based therapies.
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Affiliation(s)
| | - Xian C Li
- Immunobiology & Transplantation Research, Houston Methodist Hospital, Texas Medical Center, 6670 Bertner Avenue, R7-211, Houston, TX 77030, United States.
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38
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Nikolic I, Saksida T, Vujicic M, Stojanovic I, Stosic-Grujicic S. Anti-diabetic actions of carbon monoxide-releasing molecule (CORM)-A1: Immunomodulation and regeneration of islet beta cells. Immunol Lett 2015; 165:39-46. [PMID: 25839127 DOI: 10.1016/j.imlet.2015.03.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/19/2015] [Accepted: 03/24/2015] [Indexed: 01/01/2023]
Abstract
We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as well as beta cell regeneration. CORM-A1 (2 mg/kg/day) was administered for 10 days to mice induced with MLDS and/or depleted of low dose cyclophosphamide (CY)-sensitive FoxP3+ T regulatory (Treg) cells. Besides monitoring hyperglycaemia, ex vivo analysis of spleen, pancreatic lymph nodes (PLN) and pancreas was performed at the end of treatment. In CORM-A1-treated MLDS-induced mice the improvement of hyperglycaemia was observed only without depletion of CY-sensitive FoxP3+ Treg cells. This was accompanied by decreased levels of interleukin (IL)-12, IL-2 and early activation marker CD25 in the spleen and PLN and increased transforming growth factor (TGF)-β, resulting in reduced lymphocyte proliferation in both organs. In parallel, decreased transcript levels of IL-2, but increased mRNA expression of TGF-β, accompanied with up-regulation of Ki-67 protein expression was observed within pancreas. Together, the data suggested that besides the immunomodulatory potential, CORM-A1 probably induces beta cell regeneration.
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Affiliation(s)
- Ivana Nikolic
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia
| | - Tamara Saksida
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia
| | - Milica Vujicic
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia
| | - Ivana Stojanovic
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia
| | - Stanislava Stosic-Grujicic
- Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
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39
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Durante W. Protective Role of Heme Oxygenase-1 in Atherosclerosis. Atherosclerosis 2015. [DOI: 10.1002/9781118828533.ch29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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40
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Schumacher A, Zenclussen AC. Effects of heme oxygenase-1 on innate and adaptive immune responses promoting pregnancy success and allograft tolerance. Front Pharmacol 2015; 5:288. [PMID: 25610397 PMCID: PMC4285018 DOI: 10.3389/fphar.2014.00288] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 12/10/2014] [Indexed: 12/14/2022] Open
Abstract
The heme-degrading enzyme heme oxygenase-1 (HO-1) has cytoprotective, antioxidant, and anti-inflammatory properties. Moreover, HO-1 is reportedly involved in suppressing destructive immune responses associated with inflammation, autoimmune diseases, and allograft rejection. During pregnancy, maternal tolerance to foreign fetal antigens is a prerequisite for successful embryo implantation and fetal development. Here, HO-1 has been implicated in counteracting the overwhelming inflammatory immune responses towards fetal allo-antigens, thereby contributing to fetal acceptance. Accordingly, HO-1 ablation negatively impacts the critical steps of pregnancy such as fertilization, implantation, placentation, and fetal growth. In the present review, we summarize recent data on the immune modulatory capacity of HO-1 towards allo-antigens expressed by the semi-allogeneic fetus and organ allografts. In this regard, HO-1 has been shown to promote alloantigen tolerance by blocking dendritic cell maturation resulting in reduced T cell responses and increased numbers of regulatory T cells. Moreover, HO-1 is suggested to shift the uterine cytokine milieu towards a protective Th2 profile and protects fetal tissue from apoptosis by upregulating anti-apoptotic molecules. Thus, HO-1 is not only a pivotal regulator of the initial steps of pregnancy; but also, an important player in supporting the maternal immune system in tolerating the fetus.
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Affiliation(s)
- Anne Schumacher
- Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Germany
| | - Ana C Zenclussen
- Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University Magdeburg, Germany
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41
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Zhang L, Zhang Y, Zhong W, Di C, Lin X, Xia Z. Heme oxygenase-1 ameliorates dextran sulfate sodium-induced acute murine colitis by regulating Th17/Treg cell balance. J Biol Chem 2014; 289:26847-26858. [PMID: 25112868 DOI: 10.1074/jbc.m114.590554] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a group of autoimmune diseases characterized by nonspecific inflammation in the gastrointestinal tract. Recent investigations suggest that activation of Th17 cells and/or deficiency of regulatory T cells (Treg) is involved in the pathogenesis of IBD. Heme oxygenase (HO)-1 is a protein with a wide range of anti-inflammatory and immune regulatory function, which exerts significantly protective roles in various T cell-mediated diseases. In this study, we aim to explore the immunological regulation of HO-1 in the dextran sulfate sodium-induced model of experimental murine colitis. BALB/c mice were administered 4% dextran sulfate sodium orally; some mice were intraperitoneally pretreated with HO-1 inducer hemin or HO-1 inhibitor stannum protoporphyrin IX. The results show that hemin enhances the colonic expression of HO-1 and significantly ameliorates the symptoms of colitis with improved histological changes, accompanied by a decreased proportion of Th17 cells and increased number of Tregs in mesenteric lymph node and spleen. Moreover, induction of HO-1 down-regulates retinoic acid-related orphan receptor γt expression and IL-17A levels, while promoting Treg-related forkhead box p3 (Foxp3) expression and IL-10 levels in colon. Further study in vitro revealed that up-regulated HO-1 switched the naive T cells to Tregs when cultured under a Th17-inducing environment, which involved in IL-6R blockade. Therefore, HO-1 may exhibit anti-inflammatory activity in the murine model of acute experimental colitis via regulating the balance between Th17 and Treg cells, thus providing a possible novel therapeutic target in IBD.
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Affiliation(s)
- Liya Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Yanjie Zhang
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Wenwei Zhong
- Department of Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China
| | - Caixia Di
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Xiaoliang Lin
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and
| | - Zhenwei Xia
- Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, China and.
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42
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Zhong H, Bao W, Friedman D, Yazdanbakhsh K. Hemin controls T cell polarization in sickle cell alloimmunization. THE JOURNAL OF IMMUNOLOGY 2014; 193:102-10. [PMID: 24879794 DOI: 10.4049/jimmunol.1400105] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused RBCs with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and Th responses with higher circulating Th1 (IFN-γ(+)) cytokines in chronically transfused SCD patients with alloantibodies as compared with those without alloantibodies. Because monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to the RBC breakdown product hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T cell/monocyte cocultures from healthy volunteers through the monocyte anti-inflammatory heme-degrading enzyme heme oxygenase-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in the non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of heme oxygenase-1. Furthermore, IL-12, which contributed to a proinflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in the alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conducive to alloimmunization.
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Affiliation(s)
- Hui Zhong
- Laboratory of Complement Biology, New York Blood Center, New York, NY 10065
| | - Weili Bao
- Laboratory of Complement Biology, New York Blood Center, New York, NY 10065
| | - David Friedman
- Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
| | - Karina Yazdanbakhsh
- Laboratory of Complement Biology, New York Blood Center, New York, NY 10065;
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Increased oxidative stress and the apoptosis of regulatory T cells in obese mice but not resistant mice in response to a high-fat diet. Cell Immunol 2014; 288:39-46. [DOI: 10.1016/j.cellimm.2014.02.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 02/11/2014] [Accepted: 02/14/2014] [Indexed: 01/30/2023]
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Alijotas-Reig J, Llurba E, Gris JM. Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta 2014; 35:241-8. [PMID: 24581729 DOI: 10.1016/j.placenta.2014.02.004] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/30/2014] [Accepted: 02/04/2014] [Indexed: 02/08/2023]
Abstract
The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal-fetal interface prevented fetal allo-rejection by creating a "tolerant" microenvironment characterised by the expression of IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal-fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.
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Affiliation(s)
- J Alijotas-Reig
- Systemic Autoimmune Disease Unit, Department of Internal Medicine I, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain; Department of Medicine, Faculty of Medicine, Universitat Autonoma, Barcelona, Spain.
| | - E Llurba
- High Obstetric Risk Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain
| | - J Ma Gris
- Reproductive Medicine Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain
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46
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Holan V, Krulova M. Common and small molecules as the ultimate regulatory and effector mediators of antigen-specific transplantation reactions. World J Transplant 2013; 3:54-61. [PMID: 24392309 PMCID: PMC3879524 DOI: 10.5500/wjt.v3.i4.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 06/12/2013] [Accepted: 08/08/2013] [Indexed: 02/05/2023] Open
Abstract
In spite of intensive research, the molecular basis of allograft and xenograft rejection still remains not fully understood. The acute rejection of an allograft is associated with the intragraft Th1 cytokine response, while tolerance of an allograft or xenograft rejection is accompanied by a higher production of the Th2 cytokines interleukin (IL)-4 and IL-10. Nevertheless, these cytokines are not the final regulatory and effector molecules mediating transplantation reactions. Data indicate that the functioning of common molecules with enzymatic activities, such are inducible nitric oxide synthase (iNOS), arginase, heme oxygenase-1 (HO-1) or indoleamine-2,3-dioxygenase (IDO), the bioavailability of their substrates (L-arginine, tryptophan, heme) and the cytotoxic and regulatory actions of their small gaseous products (NO, CO) can be the ultimate mechanisms responsible for effector or regulatory reactions. Using models of transplantation immunity and tolerance we show that T cell receptor-mediated recognition of allogeneic or xenogeneic antigens as well as the balance between immunity/tolerance induces distinct cytokine production profiles. The ratio between Th1 and Th2 cytokines efficiently regulates the expression of genes for common enzymes, such as iNOS, arginase, HO-1 and IDO. These enzymes may compete for substrates, such as L-arginine or tryptophan, and the final product of their activity are small molecules (NO, CO) displaying effector or regulatory functions of the immune system. Thus, it is suggested that in spite of the high immunological specificity of transplatation reaction, the ultimate players in regulatory and effector functions could be small and common molecules.
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Brogliato AR, Moor AN, Kesl SL, Guilherme RF, Georgii JL, Peters-Golden M, Canetti C, Gould LJ, Benjamim CF. Critical role of 5-lipoxygenase and heme oxygenase-1 in wound healing. J Invest Dermatol 2013; 134:1436-1445. [PMID: 24226420 DOI: 10.1038/jid.2013.493] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 08/23/2013] [Accepted: 09/16/2013] [Indexed: 02/07/2023]
Abstract
Lipid mediators derived from 5-lipoxygenase (5-LO) metabolism can activate both pro- and anti-inflammatory pathways, but their role in wound healing remains largely unexplored. In this study we show that 5-LO knockout (5-LO(-/-)) mice exhibited faster wound healing than wild-type (WT) animals, and exhibited upregulation of heme oxygenase-1 (HO-1). Furthermore, HO-1 inhibition in 5-LO(-/-) mice abolished the beneficial effect observed. Despite the fact that 5-LO(-/-) mice exhibited faster healing, in in vitro assays both migration and proliferation of human dermal fibroblasts (HDFs) were inhibited by the 5-LO pharmacologic inhibitor AA861. No changes were observed in the expression of fibronectin, transforming growth factor (I and III), and α-smooth muscle actin (α-SMA). Interestingly, AA861 treatment significantly decreased ROS formation by stimulated fibroblasts. Similar to 5-LO(-/-) mice, induction of HO-1, but not superoxide dismutase-2 (SOD-2), was also observed in response to 5-LO (AA861) or 5-LO activating protein (MK886) inhibitors. HO-1 induction was independent of nuclear factor (erythroid derived-2) like2 (Nrf-2), cyclooxygenase 2 (COX-2) products, or lipoxin action. Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution.
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Affiliation(s)
- Ariane R Brogliato
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Andrea N Moor
- Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA; Department of Surgery, University of South Florida, Tampa, Florida, USA
| | - Shannon L Kesl
- Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA
| | - Rafael F Guilherme
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Janaína L Georgii
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marc Peters-Golden
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Claudio Canetti
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lisa J Gould
- Plastic Surgery, James A. Haley Veterans Hospital, University of South Florida, Tampa, Florida, USA; Department of Surgery, University of South Florida, Tampa, Florida, USA
| | - Claudia F Benjamim
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
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Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol 2013; 45:2843-51. [PMID: 24144577 DOI: 10.1016/j.biocel.2013.09.014] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 09/24/2013] [Accepted: 09/29/2013] [Indexed: 01/03/2023]
Abstract
Nearly a century ago, jaundiced patients were observed to have surprising and spontaneous remissions from incurable immunologic diseases including rheumatoid arthritis, allergy, and asthma. The mystery of why this phenomenon occurred remains unresolved to this day. Bilirubin has traditionally been considered an excretory product resulting from heme metabolism with little benefit to human physiology. In the past few decades, however, the salutary role of this byproduct as a potent antioxidant has been repeatedly noted. Most recently, the molecule has been found to possess immunomodulatory properties that rival its redox capacity, possibly explaining its ability to suppress inflammation. In this review, we specifically examine unconjugated bilirubin (UCB) as an immunomodulator and explore the molecular basis for its immunosuppressive effects.
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Affiliation(s)
- Sushrut Jangi
- Beth Israel Deaconess Medical Center, United States; Harvard Medical School, United States.
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Gutierrez FRS, Pavanelli WR, Medina TS, Silva GK, Mariano FS, Guedes PMM, Mineo TWP, Rossi MA, Cunha FQ, Silva JS. Haeme oxygenase activity protects the host against excessive cardiac inflammation during experimental Trypanosoma cruzi infection. Microbes Infect 2013; 16:28-39. [PMID: 24140555 DOI: 10.1016/j.micinf.2013.10.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 08/25/2013] [Accepted: 10/04/2013] [Indexed: 01/07/2023]
Abstract
The infection with Trypanosoma cruzi induces a robust cardiac inflammation that plays a pathogenic role in the development of Chagas heart disease. In this study, we aimed at investigating the effects of Haem Oxygenase (HO) during experimental infection by T. cruzi in BALB/c and C57BL/6 mice. HO has recently emerged as a key factor modulating the immune response in diverse models of inflammatory diseases. In mice with two different genetic backgrounds, the pharmacologic inhibition of HO activity with zinc-protoporphyrin IX (ZnPPIX) induced enhanced myocarditis and reduced parasitaemia, which was accompanied by an amplified production of nitric oxide and increased influx of CD4(+), CD8(+) and IFN-γ(+) cells to the myocardium in comparison with the control group. Conversely, treatment with haemin (an activator of HO) lead to a decreased number of intracardiac CD4(+) (but not CD8(+)) cells compared to the control group. The mechanism involved in these observations is a modulation of the induction of regulatory T cells, because the stimulation or inhibition of HO was parallelled by an enhanced or reduced frequency of regulatory T cells, respectively. Hence, HO may be involved in the regulation of heart tissue inflammation and could be a potential target in conceiving future therapeutic approaches for Chagas disease.
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Affiliation(s)
- Fredy R S Gutierrez
- Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, Bogotá, Colombia.
| | - Wander R Pavanelli
- Centro de Ciências Biológicas, Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Brazil; Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Tiago S Medina
- Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Grace K Silva
- Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Flávia S Mariano
- Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Paulo M M Guedes
- Departamento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil; Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Tiago W P Mineo
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Brazil; Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Marcos A Rossi
- Department of Pathology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - Fernando Q Cunha
- Department of Pharmacology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
| | - João S Silva
- Department of Biochemistry-Immunology, Ribeirão Preto School of Medicine, University of São Paulo, Brazil
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Duechler M, Peczek L, Zuk K, Zalesna I, Jeziorski A, Czyz M. The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes. Immunobiology 2013; 219:158-65. [PMID: 24091277 DOI: 10.1016/j.imbio.2013.09.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 08/30/2013] [Accepted: 09/01/2013] [Indexed: 12/30/2022]
Abstract
The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell-cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression.
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Affiliation(s)
- Markus Duechler
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 112 Sienkiewicza Street, 90-363 Lodz, Poland.
| | - Lukasz Peczek
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 112 Sienkiewicza Street, 90-363 Lodz, Poland
| | - Karolina Zuk
- Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 112 Sienkiewicza Street, 90-363 Lodz, Poland
| | - Izabela Zalesna
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland
| | - Arkadiusz Jeziorski
- Clinics for Oncological Surgery, Medical University of Lodz, 62 Pabianicka Street, 93-513 Lodz, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland
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