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Saini T, Mazumder PM. Current advancement in the preclinical models used for the assessment of diabetic neuropathy. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2727-2745. [PMID: 37987794 DOI: 10.1007/s00210-023-02802-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/17/2023] [Indexed: 11/22/2023]
Abstract
Diabetic neuropathy is one of the prevalent and debilitating microvascular complications of diabetes mellitus, affecting a significant portion of the global population. Relational preclinical animal models are essential to understand its pathophysiology and develop effective treatments. This abstract provides an overview of current knowledge and advancements in such models. Various animal models have been developed to mimic the multifaceted aspects of human diabetic neuropathy, including both type 1 and type 2 diabetes. These models involve rodents (rats and mice) and larger animals like rabbits and dogs. Induction of diabetic neuropathy in these models is achieved through chemical, genetic, or dietary interventions, such as diabetogenic agents, genetic modifications, or high-fat diets. Preclinical animal models have greatly contributed to studying the intricate molecular and cellular mechanisms underlying diabetic neuropathy. They have shed light on hyperglycemia-induced oxidative stress, neuroinflammation, mitochondrial dysfunction, and altered neurotrophic factor signaling. Additionally, these models have allowed for the investigation of morphological changes, functional alterations, and behavioral manifestations associated with diabetic neuropathy. These models have also been crucial for evaluating the efficacy and safety of potential therapeutic interventions. Novel pharmacological agents, gene therapies, stem cell-based approaches, exercise, dietary modifications, and neurostimulation techniques have been tested using these models. However, limitations and challenges remain, including physiological differences between humans and animals, complex neuropathy phenotypes, and the need for translational validation. In conclusion, preclinical animal models have played a vital role in advancing our understanding and management of diabetic neuropathy. They have enhanced our knowledge of disease mechanisms, facilitated the development of novel treatments, and provided a platform for translational research. Ongoing efforts to refine and validate these models are crucial for future treatment developments for this debilitating condition.
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Affiliation(s)
- Tanishk Saini
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, 835215, Ranchi, India
| | - Papiya Mitra Mazumder
- Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, 835215, Ranchi, India.
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Sano H, Imagawa A. Re-Enlightenment of Fulminant Type 1 Diabetes under the COVID-19 Pandemic. BIOLOGY 2022; 11:1662. [PMID: 36421377 PMCID: PMC9687436 DOI: 10.3390/biology11111662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 12/26/2024]
Abstract
Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes (T1D) that is characterized by the rapid progression to diabetic ketoacidosis against the background of rapid and almost complete pancreatic islet destruction. The HbA1c level at FT1D onset remains normal or slightly elevated despite marked hyperglycemia, reflecting the rapid clinical course of the disease, and is an important marker for diagnosis. FT1D often appears following flu-like symptoms, and there are many reports of its onset being linked to viral infections. In addition, disease-susceptibility genes have been identified in FT1D, suggesting the involvement of host factors in disease development. In most cases, islet-related autoantibodies are not detected, and histology of pancreatic tissue reveals macrophage and T cell infiltration of the islets in the early stages of FT1D, suggesting that islet destruction occurs via an immune response different from that occurring in autoimmune type 1 diabetes. From 2019, coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread worldwide and became a serious problem. Reports on the association between SARS-CoV-2 and T1D are mixed, with some suggesting an increase in T1D incidence due to the COVID-19 pandemic. When discussing the association between COVID-19 and T1D, it is also necessary to focus on FT1D. However, it is not easy to diagnose this subtype without understanding the concept. Therefore, authors hereby review the concept and the latest findings of FT1D, hoping that the association between COVID-19 and T1D will be adequately evaluated in the future.
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Affiliation(s)
- Hiroyuki Sano
- Department of Internal Medicine (I), Osaka Medical and Pharmaceutical University, Takatsuki 569-8686, Japan
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3
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Experimental animal models for diabetes and its related complications-a review. Lab Anim Res 2021; 37:23. [PMID: 34429169 PMCID: PMC8385906 DOI: 10.1186/s42826-021-00101-4] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/13/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetes mellitus, a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized by hyperglycemia, a condition with high glucose level in the blood plasma resulting from defects in insulin secretion or its action and in some cases both the impairment in secretion and also action of insulin coexist. Historically, animal models have played a critical role in exploring and describing malady pathophysiology and recognizable proof of targets and surveying new remedial specialists and in vivo medicines. In the present study, we reviewed the experimental models employed for diabetes and for its related complications. This paper reviews briefly the broad chemical induction of alloxan and streptozotocin and its mechanisms associated with type 1 and type 2 diabetes. Also we highlighted the different models in other species and other animals.
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Stafford JD, Yeo CT, Corbett JA. Inhibition of oxidative metabolism by nitric oxide restricts EMCV replication selectively in pancreatic beta-cells. J Biol Chem 2020; 295:18189-18198. [PMID: 33100269 PMCID: PMC7939444 DOI: 10.1074/jbc.ra120.015893] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/08/2020] [Indexed: 01/27/2023] Open
Abstract
Environmental factors, such as viral infection, are proposed to play a role in the initiation of autoimmune diabetes. In response to encephalomyocarditis virus (EMCV) infection, resident islet macrophages release the pro-inflammatory cytokine IL-1β, to levels that are sufficient to stimulate inducible nitric oxide synthase (iNOS) expression and production of micromolar levels of the free radical nitric oxide in neighboring β-cells. We have recently shown that nitric oxide inhibits EMCV replication and EMCV-mediated β-cell lysis and that this protection is associated with an inhibition of mitochondrial oxidative metabolism. Here we show that the protective actions of nitric oxide against EMCV infection are selective for β-cells and associated with the metabolic coupling of glycolysis and mitochondrial oxidation that is necessary for insulin secretion. Inhibitors of mitochondrial respiration attenuate EMCV replication in β-cells, and this inhibition is associated with a decrease in ATP levels. In mouse embryonic fibroblasts (MEFs), inhibition of mitochondrial metabolism does not modify EMCV replication or decrease ATP levels. Like most cell types, MEFs have the capacity to uncouple the glycolytic utilization of glucose from mitochondrial respiration, allowing for the maintenance of ATP levels under conditions of impaired mitochondrial respiration. It is only when MEFs are forced to use mitochondrial oxidative metabolism for ATP generation that mitochondrial inhibitors attenuate viral replication. In a β-cell selective manner, these findings indicate that nitric oxide targets the same metabolic pathways necessary for glucose stimulated insulin secretion for protection from viral lysis.
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Affiliation(s)
- Joshua D Stafford
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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5
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Genetic Susceptibility of the Host in Virus-Induced Diabetes. Microorganisms 2020; 8:microorganisms8081133. [PMID: 32727064 PMCID: PMC7464158 DOI: 10.3390/microorganisms8081133] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/07/2020] [Accepted: 07/24/2020] [Indexed: 12/13/2022] Open
Abstract
Enteroviruses, especially Coxsackie B viruses, are among the candidate environmental factors causative of type 1 diabetes. Host genetic factors have an impact on the development of virus-induced diabetes (VID). Host background, in terms of whether the host is prone to autoimmunity, should also be considered when analyzing the role of target genes in VID. In this review, we describe the genetic susceptibility of the host based on studies in humans and VID animal models. Understanding the host genetic factors should contribute not only to revealing the mechanisms of VID development, but also in taking measures to prevent VID.
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Rutman AK, Negi S, Gasparrini M, Hasilo CP, Tchervenkov J, Paraskevas S. Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes. Endocrinology 2018; 159:3834-3847. [PMID: 30307543 DOI: 10.1210/en.2018-00649] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 10/01/2018] [Indexed: 12/14/2022]
Abstract
The autoimmune response that characterizes type 1 diabetes (T1D) has no clear cause. Extracellular vesicles (EVs) play an important role in triggering the immune response in other contexts. Here, we propose a model by which EVs isolated from human islets stimulate proinflammatory immune responses and lead to peripheral blood mononuclear cell (PBMC) activation. We show that human islet EVs are internalized by monocytes and B cells and lead to an increase in T-helper 1, 2, and 17 cytokine expression, as well as T and B cell proliferation. Importantly, we demonstrate memory T and B cell activation by EVs selectively in PBMCs of patients with T1D. Additionally, human islet EVs induce an increase in antibodies against glutamic acid decarboxylase 65 (GAD65) in T1D PBMCs. Furthermore, pretreatment of T1D PBMCs with ibrutinib, an inhibitor of Bruton tyrosine kinase, dampens EV-induced memory B cell activation and GAD65 antibody production. Collectively, our findings indicate a role for human islet EVs in mediating activation of B and T cells and GAD65 autoantibody production.
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Affiliation(s)
- Alissa K Rutman
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
| | - Sarita Negi
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
| | - Marco Gasparrini
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
| | - Craig P Hasilo
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
| | - Jean Tchervenkov
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
| | - Steven Paraskevas
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montréal, Québec, Canada
- Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
- Canadian National Transplant Research Program, Edmonton, Alberta, Canada
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7
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High-density lipoprotein immunomodulates the functional activities of macrophage and cytokines produced during ex vivo macrophage-CD4 + T cell crosstalk at the recent-onset human type 1 diabetes. Cytokine 2017; 96:59-70. [DOI: 10.1016/j.cyto.2017.03.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 02/08/2017] [Accepted: 03/01/2017] [Indexed: 12/31/2022]
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Shaheen ZR, Naatz A, Corbett JA. CCR5-Dependent Activation of mTORC1 Regulates Translation of Inducible NO Synthase and COX-2 during Encephalomyocarditis Virus Infection. THE JOURNAL OF IMMUNOLOGY 2015; 195:4406-14. [PMID: 26408666 DOI: 10.4049/jimmunol.1500704] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 08/27/2015] [Indexed: 11/19/2022]
Abstract
Encephalomyocarditis virus (EMCV) infection of macrophages results in the expression of a number of inflammatory and antiviral genes, including inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. EMCV-induced macrophage activation has been shown to require the presence of CCR5 and the activation of PI3K-dependent signaling cascades. The purpose of this study was to determine the role of PI3K in regulating the macrophage responses to EMCV. We show that PI3K regulates EMCV-stimulated iNOS and COX-2 expression by two independent mechanisms. In response to EMCV infection, Akt is activated and regulates the translation of iNOS and COX-2 through the mammalian target of rapamycin complex (mTORC)1. The activation of mTORC1 during EMCV infection is CCR5-dependent and appears to function in a manner that promotes the translation of iNOS and COX-2. CCR5-dependent mTORC1 activation functions as an antiviral response, as mTORC1 inhibition increases the expression of EMCV polymerase. PI3K also regulates the transcriptional induction of iNOS and COX-2 in response to EMCV infection by a mechanism that is independent of Akt and mTORC1 regulation. These findings indicate that macrophage expression of the inflammatory genes iNOS and COX-2 occurs via PI3K- and Akt-dependent translational control of mTORC1 and PI3K-dependent, Akt-independent transcriptional control.
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Affiliation(s)
- Zachary R Shaheen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee WI 53226
| | - Aaron Naatz
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee WI 53226
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee WI 53226
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Shaheen ZR, Corbett JA. Macrophage Expression of Inflammatory Genes in Response to EMCV Infection. Biomolecules 2015; 5:1938-54. [PMID: 26295266 PMCID: PMC4598781 DOI: 10.3390/biom5031938] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/06/2015] [Accepted: 08/08/2015] [Indexed: 12/24/2022] Open
Abstract
The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression.
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Affiliation(s)
- Zachary R Shaheen
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI 53226, USA.
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, 8701 W. Watertown Plank Rd, Milwaukee, WI 53226, USA.
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10
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Dhuria RS, Singh G, Kaur A, Kaur R, Kaur T. Current status and patent prospective of animal models in diabetic research. Adv Biomed Res 2015; 4:117. [PMID: 26261819 PMCID: PMC4513317 DOI: 10.4103/2277-9175.157847] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/15/2014] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is a heterogeneous complex metabolic disorder with multiple etiology which characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action or both. The widespread occurrence of diabetes throughout the world has increased dramatically over the past few years. For better understanding, appropriate animal models that closely mimic the changes in humans needed, as vital tool for understanding the etiology and pathogenesis of the disease at the cellular/molecular level and for preclinical testing of drugs. This review aims to describe the animal models of type-1 diabetes (T1Ds) and T2Ds to mimic the causes and progression of the disease in humans. And also we highlight patent applications published in the last few years related to animal models in diabetes as an important milestone for future therapies that are aim to treating diabetes with specific symptoms and complications.
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Affiliation(s)
- Radhey S. Dhuria
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Gurpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Anudeep Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Ramandeep Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Tanurajvir Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
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11
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Yi SS. Effects of exercise on brain functions in diabetic animal models. World J Diabetes 2015; 6:583-597. [PMID: 25987956 PMCID: PMC4434079 DOI: 10.4239/wjd.v6.i4.583] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 01/16/2015] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Human life span has dramatically increased over several decades, and the quality of life has been considered to be equally important. However, diabetes mellitus (DM) characterized by problems related to insulin secretion and recognition has become a serious health problem in recent years that threatens human health by causing decline in brain functions and finally leading to neurodegenerative diseases. Exercise is recognized as an effective therapy for DM without medication administration. Exercise studies using experimental animals are a suitable option to overcome this drawback, and animal studies have improved continuously according to the needs of the experimenters. Since brain health is the most significant factor in human life, it is very important to assess brain functions according to the different exercise conditions using experimental animal models. Generally, there are two types of DM; insulin-dependent type 1 DM and an insulin-independent type 2 DM (T2DM); however, the author will mostly discuss brain functions in T2DM animal models in this review. Additionally, many physiopathologic alterations are caused in the brain by DM such as increased adiposity, inflammation, hormonal dysregulation, uncontrolled hyperphagia, insulin and leptin resistance, and dysregulation of neurotransmitters and declined neurogenesis in the hippocampus and we describe how exercise corrects these alterations in animal models. The results of changes in the brain environment differ according to voluntary, involuntary running exercises and resistance exercise, and gender in the animal studies. These factors have been mentioned in this review, and this review will be a good reference for studying how exercise can be used with therapy for treating DM.
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12
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Coppieters KT, Boettler T, von Herrath M. Virus infections in type 1 diabetes. Cold Spring Harb Perspect Med 2013; 2:a007682. [PMID: 22315719 DOI: 10.1101/cshperspect.a007682] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The precise etiology of type 1 diabetes (T1D) is still unknown, but viruses have long been suggested as a potential environmental trigger for the disease. However, despite decades of research, the body of evidence supporting a relationship between viral infections and initiation or acceleration of islet autoimmunity remains largely circumstantial. The most robust association with viruses and T1D involves enterovirus species, of which some strains have the ability to induce or accelerate disease in animal models. Several hypotheses have been formulated to mechanistically explain how viruses may affect islet autoimmunity and β-cell decay. The recent observation that certain viral infections, when encountered at the right time and infectious dose, can prevent autoimmune diabetes illustrates that potential relationships may be more complex than previously thought. Here, we provide a concise summary of data obtained in mouse models and humans, and identify future avenues toward a better characterization of the association between viruses and T1D.
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Affiliation(s)
- Ken T Coppieters
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA
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13
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Abstract
Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients.
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Wang Y, Swiecki M, McCartney SA, Colonna M. dsRNA sensors and plasmacytoid dendritic cells in host defense and autoimmunity. Immunol Rev 2011; 243:74-90. [PMID: 21884168 DOI: 10.1111/j.1600-065x.2011.01049.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The innate immune system detects viruses through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines. As viruses vary tremendously in size, structure, genomic composition, and tissue tropism, multiple sensors are required to detect their presence in various cell types and tissues. In this review, we summarize current knowledge of the diversity, specificity, and signaling pathways downstream of viral sensors and ask whether two distinct sensors that recognize the same viral component are complementary, compensatory, or simply redundant. We also discuss why viral sensors are differentially distributed in distinct cell types and whether a particular cell type dominates the IFN-I response during viral infection. Finally, we review evidence suggesting that inappropriate signaling through viral sensors may induce autoimmunity. The picture emerging from these studies is that disparate viral sensors in different cell types form a dynamic and integrated molecular network that can be exploited for improving vaccination and therapeutic strategies for infectious and autoimmune diseases.
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Affiliation(s)
- Yaming Wang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Swiecki M, McCartney SA, Wang Y, Colonna M. TLR7/9 versus TLR3/MDA5 signaling during virus infections and diabetes. J Leukoc Biol 2011; 90:691-701. [PMID: 21844166 DOI: 10.1189/jlb.0311166] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
IFN-I are pleiotropic cytokines that impact innate and adaptive immune responses. In this article, we discuss TLR7/9 versus TLR3/MDA5 signaling in antiviral responses and diabetes. pDCs are thought to have a critical role in antiviral defense because of their ability to rapidly secrete large amounts of IFN-I through TLR7/9 signaling. A recent study demonstrates that although pDCs are a source of IFN-I in vivo, their overall contribution to viral containment is limited and time-dependent, such that additional cellular sources of IFN-I are required to fully control viral infections. dsRNA sensors, such as TLR3 and MDA5, provide another important trigger for antiviral IFN-I responses, which can be exploited to enhance immune responses to vaccines. In the absence of infection, IFN-I production by pDCs or from signaling through dsRNA sensors has been implicated in the pathogenesis of autoimmune diseases such as diabetes. However, recent data demonstrate that IFN-I production via TLR3 and MDA5 is critical to counter diabetes caused by a virus with preferential tropism for pancreatic β-cells. This highlights the complexity of the host antiviral response and how multiple cellular and molecular components balance protective versus pathological responses.
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Affiliation(s)
- Melissa Swiecki
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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Sano H, Terasaki J, Mishiba Y, Imagawa A, Hanafusa T. Exendin-4, a glucagon-like peptide-1 receptor agonist, suppresses pancreatic β-cell destruction induced by encephalomyocarditis virus. Biochem Biophys Res Commun 2011; 404:756-61. [DOI: 10.1016/j.bbrc.2010.12.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Accepted: 12/02/2010] [Indexed: 01/07/2023]
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Abstract
The development of type 1 diabetes involves a complex interaction between pancreatic beta-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.
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Role of nitric oxide in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. J Virol 2009; 83:8004-11. [PMID: 19535454 DOI: 10.1128/jvi.00205-09] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic beta cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in beta-cell destruction by producing soluble mediators such as interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO). To investigate the role of NO and inducible NO synthase (iNOS) in the development of diabetes in EMC-D virus-infected mice, we infected iNOS-deficient DBA/2 mice with EMC-D virus (2 x 10(2) PFU/mouse). Mean blood glucose levels in EMC-D virus-infected iNOS-deficient mice and wild-type mice were 205.5 and 466.7 mg/dl, respectively. Insulitis and macrophage infiltration were reduced in islets of iNOS-deficient mice compared with wild-type mice at 3 days after EMC-D virus infection. Apoptosis of beta cells was decreased in iNOS-deficient mice, as evidenced by reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. There were no differences in mRNA expression of antiapoptotic molecules Bcl-2, Bcl-xL, Bcl-w, Mcl-1, cIAP-1, and cIAP-2 between wild-type and iNOS-deficient mice, whereas expression of proapoptotic Bax and Bak mRNAs was significantly decreased in iNOS-deficient mice. Expression of IL-1beta and TNF-alpha mRNAs was significantly decreased in both islets and macrophages of iNOS-deficient mice compared with wild-type mice after EMC-D virus infection. Nuclear factor kappaB was less activated in macrophages of iNOS-deficient mice after virus infection. We conclude that NO plays an important role in the activation of macrophages and apoptosis of pancreatic beta cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and beta-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.
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Kounoue E, Izumi KI, Ogawa S, Kondo S, Katsuta H, Akashi T, Niho Y, Harada M, Tamiya S, Kurisaki H, Nagafuchi S. The significance of T cells, B cells, antibodies and macrophages against encephalomyocarditis (EMC)-D virus-induced diabetes in mice. Arch Virol 2008; 153:1223-31. [PMID: 18500429 DOI: 10.1007/s00705-008-0106-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Accepted: 04/11/2008] [Indexed: 11/26/2022]
Abstract
In order to clarify the significance of protective mechanisms against encephalomyocarditis (EMC) virus-induced diabetes in mice, we studied the relative importance of T cells, B cells, antibodies and macrophages in the prevention of virus-induced diabetes. Neither T cell-deficient athymic nude mice nor B cell-deficient microMT/microMT mice showed an enhanced clinical course of EMC-D virus-induced diabetes, indicating that neither T cells nor B cells played a major role in the protection against EMC-D-virus-induced diabetes. Transfer of a large amount of antiserum to EMC-D-virus-infected mice protected the development of diabetes only when transferred within 36 h of infection, the timing of which was earlier than that for the production of natural neutralizing antibodied. Since pretreatment of mice with the macrophage-activating immunopotentiator Corynebacterium parvum (CP) completely prevented the development of diabetes, we studied the clinical outcome of EMC-D-virus-infected mice pretreated with CP. Mice treated with CP showed reduced proliferation of EMC-D virus in the affected organs, including the pancreas, while the levels of development of neutralizing antibody and serum interferon were not enhanced compared with the controls. Finally, we studied the macrophages derived from mice pretreated with CP and found that they inhibited the growth of EMC-D virus in vitro more than those derived from non-treated and thioglycolate-treated mice. Taken together, it can be suggested that neither T cells nor B cells, which have to do with adaptive immunity, play a significant role in the pathogenesis of EMC-D-virus-induced diabetes, while innate immunity, which is dependent on activated macrophages, contributes to in vivo resistance against EMC-D-virus-induced diabetes.
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Affiliation(s)
- Etsushi Kounoue
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
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20
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Abram CL, Lowell CA. The diverse functions of Src family kinases in macrophages. FRONT BIOSCI-LANDMRK 2008; 13:4426-50. [PMID: 18508521 DOI: 10.2741/3015] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways.
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Affiliation(s)
- Clare L Abram
- Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA
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21
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van der Werf N, Kroese FGM, Rozing J, Hillebrands JL. Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 2007; 23:169-83. [PMID: 17103489 DOI: 10.1002/dmrr.695] [Citation(s) in RCA: 144] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
During the last decades, the incidence of type 1 diabetes (T1D) has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetical factors environmental perturbations (including viral infections) are also involved in the pathogenesis of T1D. T1D has been associated with viral infections including enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus (CMV). Although correlations between clinical presentation with T1D and the occurrence of a viral infection that precedes the development of overt disease have been recognized, causalities between viruses and the diabetogenic process are still elusive and difficult to prove in humans. The use of experimental animal models is therefore indispensable, and indeed more insight in the mechanism by which viruses can modulate diabetogenesis has been provided by studies in rodent models for T1D such as the biobreeding (BB) rat, nonobese diabetic (NOD) mouse or specific transgenic mouse strains. Data from experimental animals as well as in vitro studies indicate that various viruses are clearly able to modulate the development of T1D via different mechanisms, including direct beta-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells and molecular mimicry. Data obtained in rodents and in vitro systems have improved our insight in the possible role of viral infections in the pathogenesis of human T1D. Future studies will hopefully reveal which human viruses are causally involved in the induction of T1D and this knowledge may provide directions on how to deal with viral infections in diabetes-susceptible individuals in order to delay or even prevent the diabetogenic process.
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Affiliation(s)
- Nienke van der Werf
- Department of Cell Biology, Immunology Section, University Medical Center Groningen, University of Groningen, The Netherlands
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22
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Abstract
More than 10 viruses have been reported to be associated with the development of type 1 diabetes-like symptoms in animals, with the best evidence coming from studies on the D variant of encephalomyocarditis (EMC-D) virus in mice and Kilham rat virus (KRV) in rats. A high titer of EMC-D viral infection results in the development of diabetes within 3 days, primarily due to the rapid destruction of beta cells by viral replication within the cells. A low titer of EMC-D viral infection results in the recruitment of macrophages to the islets. Soluble mediators produced by activated macrophages play a critical role in the destruction of residual beta cells. A single amino acid at position 776 of the EMC viral genome controls the diabetogenicity of the virus. In contrast, KRV causes autoimmune type 1 diabetes in diabetes-resistant BioBreeding (DR-BB) rats without direct infection of beta cells. Macrophages play an important role in the development of diabetes in KRV-infected DR-BB rats. As well, KRV infection preferentially activates effector T cells, such as Th1-like CD45RC(+)CD4(+) T cells and CD8(+) T cells, and downregulates regulatory T cells, such as Th2-like CD45RC(-)CD4(+) T cells. This results in the breakdown of the immune balance, contributing to the development of diabetes in KRV-infected DR-BB rats.
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Affiliation(s)
- Ji-Won Yoon
- Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, North Chicago, IL 60064, USA
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23
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Abstract
Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells. Genetic factors are believed to be a major component for the development of T1D, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. Viruses are one environmental factor that is implicated in the pathogenesis of T1D. To date, 14 different viruses have been reported to be associated with the development of T1D in humans and animal models. Viruses may be involved in the pathogenesis of T1D in at least two distinct ways: by inducing beta cell-specific autoimmunity, with or without infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic infection and destruction of the beta cells (e.g. encephalomyocarditis virus in mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV, bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus, cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the destruction of beta cells by cytolytic infection, encephalomyocarditis virus, mengovirus and Coxsackie B viruses are discussed. In addition, a review of transgenic animal models for virus-induced autoimmune diabetes is included, particularly with regard to lymphocytic choriomeningitis virus, influenza viral proteins and the Epstein-Barr viral receptor. Finally, the prevention of autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis virus is discussed.
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Affiliation(s)
- Hee-Sook Jun
- Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Mechanisms of beta-cell death in response to double-stranded (ds) RNA and interferon-gamma: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis. THE AMERICAN JOURNAL OF PATHOLOGY 2001; 159:273-83. [PMID: 11438474 PMCID: PMC1850419 DOI: 10.1016/s0002-9440(10)61693-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate beta-cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs beta-cell function and induces beta-cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates beta-cell DNA damage and apoptosis without impairing islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-gamma stimulates DNA damage, apoptosis, and necrosis of islet cells, and this damage is associated with the inhibition of glucose-stimulated insulin secretion. Nitric oxide mediates the inhibitory and destructive actions of poly IC + IFN-gamma on insulin secretion and islet cell necrosis. Inhibitors of nitric oxide synthase, aminoguanidine, and N(G)-monomethyl-L-arginine, attenuate poly IC + IFN-gamma-induced DNA damage to levels observed in response to poly IC alone, prevent islet cell necrosis, and prevent the inhibitory actions on glucose-stimulated insulin secretion. N(G)-monomethyl-L-arginine fails to prevent poly IC- and poly IC + IFN-gamma-induced islet cell apoptosis. PKR, the dsRNA-dependent protein kinase that mediates the antiviral response in infected cells, is required for poly IC- and poly IC + IFN-gamma-induced islet cell apoptosis, but not nitric oxide-mediated islet cell necrosis. Alone, poly IC fails to stimulate DNA damage in islets isolated from PKR-deficient mice; however, nitric oxide-dependent DNA damage induced by the combination of poly IC + IFN-gamma is not attenuated by the genetic absence of PKR. These findings indicate that dsRNA stimulates PKR-dependent islet cell apoptosis, an event that is associated with normal islet secretory function. In contrast, poly IC + IFN-gamma-induced inhibition of glucose-stimulated insulin secretion and islet cell necrosis are events that are mediated by islet production of nitric oxide. These findings suggest that at least one IFN-gamma-induced antiviral response (islet cell necrosis) is mediated through a PKR-independent pathway.
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25
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Choi KS, Jun HS, Kim HN, Park HJ, Eom YW, Noh HL, Kwon H, Kim HM, Yoon JW. Role of Hck in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. J Virol 2001; 75:1949-57. [PMID: 11160694 PMCID: PMC115141 DOI: 10.1128/jvi.75.4.1949-1957.2001] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Soluble mediators such as interleukin-1beta, tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic beta cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of beta cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56(Hck), p55(Fgr), and p56/p53(Lyn) in macrophages from DBA/2 mice infected with the virus. We found that p59/p56(Hck) showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55(Fgr) and p56/p53(Lyn) did not. The p59/p56(Hck) activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56(Hck) activity and almost complete inhibition of the production of TNF-alpha and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56(Hck), plays an important role in the activation of macrophages and the subsequent production of TNF-alpha and nitric oxide, leading to the destruction of pancreatic beta cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.
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Affiliation(s)
- K S Choi
- Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea
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26
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Melo RC, Machado CR. Trypanosoma cruzi: peripheral blood monocytes and heart macrophages in the resistance to acute experimental infection in rats. Exp Parasitol 2001; 97:15-23. [PMID: 11207110 DOI: 10.1006/expr.2000.4576] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The contribution of mononuclear phagocytes to host resistance against acute Chagas disease has been studied in vivo in a rat model inoculated with Trypanosoma cruzi, Y strain. Acute T. cruzi infection triggered a dramatic increase (937%) in peripheral blood monocyte number at day 12 of infection. At this point, histological analysis of the heart showed high parasitism and diffuse and a moderate to intense mononuclear inflammatory process. Ultrastructural study revealed a large number of macrophages, in addition to lymphocytes and undiffer entiated cells. Clusters of macrophages exhibited different morphologi cal phenotypes, with evident signs of activation (increase in size, surface rufflings, and amount of cytoplasmic organelles). Cell-to-cell contacts involving macrophages and lymphocytes or macrophages and mono cytes were observed. Depletion of macrophages by treatment with silica, a selective cytotoxic agent for these cells, caused a significant increase in the number of amastigote nests in cardiomyocytes. The present findings indicate that the early phase of infection with T. cruzi induces rapid production, maturation, and activation of the monocyte/macrophage system so as to control T. cruzi replication, emphasizing the crucial role for macrophages in the rat resistance to Chagas disease.
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Affiliation(s)
- R C Melo
- Laboratory of Cellular Biology, Federal University of Juiz de Fora (UFJF), Juiz de Fora, MG, 36036-330, Brazil.
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27
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Hirasawa K, Jun HS, Han HS, Zhang ML, Hollenberg MD, Yoon JW. Prevention of encephalomyocarditis virus-induced diabetes in mice by inhibition of the tyrosine kinase signalling pathway and subsequent suppression of nitric oxide production in macrophages. J Virol 1999; 73:8541-8. [PMID: 10482607 PMCID: PMC112874 DOI: 10.1128/jvi.73.10.8541-8548.1999] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/1999] [Accepted: 06/16/1999] [Indexed: 11/20/2022] Open
Abstract
Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta-cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.
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Affiliation(s)
- K Hirasawa
- Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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28
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Melo RC. Depletion of immune effector cells induces myocardial damage in the acute experimental Trypanosoma cruzi infection: ultrastructural study in rats. Tissue Cell 1999; 31:281-90. [PMID: 10481300 DOI: 10.1054/tice.1999.0040] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The contribution of radiosensitive cells and macrophages to myocardial immunopathology has been studied in rats inoculated with Trypanosoma cruzi, Y strain. Immunodepression was induced by gamma irradiation and depletion of radioresistant macrophages was achieved by silica, a selective cytotoxic agent for macrophages. Irradiated or silica treated rats and age-matched controls were sacrificed at day 12 of infection so as to study the heart by light and electron microscopy. In the infected controls, damaged cardiomyocytes were directly related to tissue parasitism; inflammatory cells, predominantly lymphocytes and macrophages, were present. The drastic depletion of radiosensitive cells (lymphocytes and granulocytes), as well as the depletion of macrophages by silica, induced cardiomyocytes damage during the acute infection, exacerbating the lesions seen in the infected controls. In the irradiated-infected and silica treated-infected animals, degenerating cardiomyocytes, parasitized or not, were frequently observed, displaying evident signs of cytoplasmic and nuclear damage. Some signs of cardiomyocyte damage (irregular distribution of glycogen particles and myofibrils with shrinkage and aggregation of Z bands) were present only in silica treated-infected animals. The findings suggest that immune effector cells may not play a major role in the cardiomyocyte damage induced by acute. Chagas disease, arguing against the autoimmune etiology of Chagasic cardiomyopathy.
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Affiliation(s)
- R C Melo
- Department of Biology, Federal University of Juiz de Fora, Brazil.
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29
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Abstract
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease whose etiology is complex. Both genetic susceptibility, which is polygenic, and environmental factors, including virus infections, appear to be involved in the development of IDDM. In this review, we have tried to balance the discussion of diabetes by examining both immunological and virological perspectives. Several mouse models, including viral and non-viral models, have been used to study diabetes. For this review, we include lessons gleaned from the non-obese diabetic (NOD) mouse and from mouse models of coxsackievirus- and encephalomyocarditis-virus-induced diabetes. Finally, we present a multi-stage model in which several viral infections, including the coxsackieviruses, are postulated to play a role in the autoimmune destruction of pancreatic beta cells.
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Affiliation(s)
- A I Ramsingh
- David Axelrod Institute, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-2002, USA
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30
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Hirasawa K, Jun HS, Maeda K, Kawaguchi Y, Itagaki S, Mikami T, Baek HS, Doi K, Yoon JW. Possible role of macrophage-derived soluble mediators in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice. J Virol 1997; 71:4024-31. [PMID: 9094680 PMCID: PMC191555 DOI: 10.1128/jvi.71.5.4024-4031.1997] [Citation(s) in RCA: 51] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Pancreatic islets from DBA/2 mice infected with the D variant of encephalomyocarditis (EMC-D) virus revealed lymphocytic infiltration with moderate to severe destruction of pancreatic beta cells. Our previous studies showed that the major population of infiltrating cells at the early stages of infection is macrophages. The inactivation of macrophages prior to viral infection resulted in the prevention of diabetes, whereas activation of macrophages prior to viral infection resulted in the enhancement of beta-cell destruction. This investigation was initiated to determine whether macrophage-produced soluble mediators play a role in the destruction of pancreatic beta cells in mice infected with a low dose of EMC-D virus. When we examined the expression of the soluble mediators interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in the pancreatic islets, we found that these mediators were clearly expressed at an early stage of insulitis and that this expression was evident until the development of diabetes. We confirmed the expression of these mediators by in situ hybridization with digoxigenin-labelled RNA probes or immunohistochemistry in the pancreatic islets. Mice treated with antibody against IL-1beta or TNF-alpha or with the iNOS inhibitor aminoguanidine exhibited a significant decrease in the incidence of diabetes. Mice treated with a combination of anti-IL-1beta antibody, anti-TNF-alpha antibody, and aminoguanidine exhibited a greater decrease in the incidence of disease than did mice treated with one of the antibodies or aminoguanidine. On the basis of these observations, we conclude that macrophage-produced soluble mediators play an important role in the destruction of pancreatic beta cells, resulting in the development of diabetes in mice infected with a low dose of EMC-D virus.
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Affiliation(s)
- K Hirasawa
- Department of Microbiology and Infectious Disease, Faculty of Medicine, University of Calgary, Alberta, Canada
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31
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Affiliation(s)
- J W Yoon
- Julia McFarlane Diabetes Research Centre, University of Calgary, Alberta, Canada
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32
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Dan K, Seto Y, Fujita T, Asaba Y, Takei I, Fujita H, Kato R. Characterization of insulin-dependent diabetes mellitus induced by a new variant (DK-27) of encephalomyocarditis virus in DBA/2 mice. Exp Anim 1995; 44:211-8. [PMID: 7556422 DOI: 10.1538/expanim.44.211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
A murine diabetes mellitus induced with a new diabetogenic variant (DK-27) which we isolated from the M variant of the encephalomyocarditis (EMC) virus was characterized. Male DBA/2 mice (9.5 weeks old) were infected with various infectious doses of DK-27 intraperitoneally. Blood glucose and insulin levels were examined in association with the viral replication. Pancreatic pathology and hormone contents and stable hemoglobin A1c (St-A1c) levels were also examined on the final day of observation (35 days of post-infection). In infected mice, blood glucose levels rapidly elevated at 72 hr, slightly decreased between 7 and 10 days and finally became sustained hyperglycemia. On the other hand, blood insulin levels elevated at 48 hr, promptly decreased, and subsequently became sustained hypoinsulinemia. Viral replication in pancreases reached the highest titers at 48 hr and rapidly disappeared with all infectious doses used. Pancreatic insulin contents in infected mice were not detectable, and glucagon contents were not affected. In pathological examination, atrophy of islets and marked diminution of B-cells were observed, and A-cells occupied the major part of an infected islet. St-A1c levels reflected lasting hyperglycemia. These findings show that DK-27 causes insulin-dependent diabetes mellitus by the specific and direct destruction of pancreatic B-cells in susceptible mice. Such a diabetic model mouse will be useful for therapeutic studies.
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Affiliation(s)
- K Dan
- Division of Chemotherapy, School of Medicine, Keio University, Tokyo, Japan
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33
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Josefsen K, Nielsen H, Lorentzen S, Damsbo P, Buschard K. Circulating monocytes are activated in newly diagnosed type 1 diabetes mellitus patients. Clin Exp Immunol 1994; 98:489-93. [PMID: 7994912 PMCID: PMC1534494 DOI: 10.1111/j.1365-2249.1994.tb05517.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Investigations in the BB rat and the non-obese diabetic (NOD) mouse have provided substantial evidence for the involvement of the monocyte/macrophage system in the development of type 1 diabetes mellitus. However, it is not known whether monocytes play the same role in the pathogenesis of human type 1 diabetes. We investigated this problem in a longitudinal study of 29 recent-onset type 1 diabetes mellitus patients. Monocyte chemotaxis, phagocytosis and superoxide production as well as metabolic and haematological parameters were studied immediately after diagnosis and 6 months later. At diagnosis the patients had activated casein and C5a chemotaxis (casein 70 +/- 9 versus 150 +/- 5 (mean +/- s.e.m.), P < 0.001; C5a 137 +/- 10 versus 158 +/- 5, P < 0.05 (activation immobilizes monocytes, reducing the measured values)), and activated superoxide production (3.6 +/- 0.3 versus 3.0 +/- 0.3, P < 0.05). After 6 months casein chemotaxis (115 +/- 16 versus 150 +/- 5, P < 0.05) and Candida phagocytosis (3.3 +/- 0.1 versus 2.8 +/- 0.2, P < 0.001) were still activated. There was no correlation with other clinical or paraclinical parameters. We conclude that the circulating monocytes in newly diagnosed type 1 diabetes patients are activated. It is reasonable to expect that monocytes at the local site of inflammation in pancreas are even further activated. This could play a pathogenic role in beta cell destruction.
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Affiliation(s)
- K Josefsen
- Bartholin Instituttet, Kommunehospitalet, Copenhagen K, Denmark
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34
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Curiel RE, Miller MH, Ishikawa R, Thomas DC, Bigley NJ. Does the gender difference in interferon production seen in picornavirus-infected spleen cell cultures from ICR Swiss mice have any in vivo significance? JOURNAL OF INTERFERON RESEARCH 1993; 13:387-95. [PMID: 7512115 DOI: 10.1089/jir.1993.13.387] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Splenocyte cultures from female ICR Swiss mice produced greater interferon (IFN) levels, particularly IFN-gamma, than did cultures from males by 12 h post-infection (pi) with the D variant of encephalomyocarditis virus (EMCV-D). This early IFN-gamma is produced by natural killer (NK)-like cells and is dependent on plastic adherent cells and IFN-alpha/beta. In this study, we evaluated the significance of this observation on the innate resistance of ICR Swiss females to EMCV-D-mediated disease. Treatment of females with rabbit anti-mouse IFN-alpha/beta serum rendered them susceptible to the diabetogenicity of EMCV-D. Although sera from both sexes of ICR Swiss mice exhibited peak IFN levels day 3 pi, IFN-gamma was present in the sera of males at only 1 day pi and in the sera of females at days 1-3 pi. Females cleared virus from the circulation by day 2 pi, 1 day earlier than did males. Flow cytometric evaluations of lymphoid cell phenotypes in spleens and pancreata of infected mice revealed that percentages of L3T4+ cells were significantly decreased only in spleens from males at day 1 pi and were diminished along with Ly2+ cells in pancreata of males at 7 days pi, suggesting that T-cell responses were impaired in virus-infected males.
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Affiliation(s)
- R E Curiel
- Department of Microbiology and Immunology, Wright State University, Dayton, OH 45435
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