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Popotas A, Casimir GJ, Corazza F, Lefèvre N. Sex-related immunity: could Toll-like receptors be the answer in acute inflammatory response? Front Immunol 2024; 15:1379754. [PMID: 38835761 PMCID: PMC11148260 DOI: 10.3389/fimmu.2024.1379754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/06/2024] [Indexed: 06/06/2024] Open
Abstract
An increasing number of studies have highlighted the existence of a sex-specific immune response, wherein men experience a worse prognosis in cases of acute inflammatory diseases. Initially, this sex-dependent inflammatory response was attributed to the influence of sex hormones. However, a growing body of evidence has shifted the focus toward the influence of chromosomes rather than sex hormones in shaping these inflammatory sex disparities. Notably, certain pattern recognition receptors, such as Toll-like receptors (TLRs), and their associated immune pathways have been implicated in driving the sex-specific immune response. These receptors are encoded by genes located on the X chromosome. TLRs are pivotal components of the innate immune system, playing crucial roles in responding to infectious diseases, including bacterial and viral pathogens, as well as trauma-related conditions. Importantly, the TLR-mediated inflammatory responses, as indicated by the production of specific proteins and cytokines, exhibit discernible sex-dependent patterns. In this review, we delve into the subject of sex bias in TLR activation and explore its clinical implications relatively to both the X chromosome and the hormonal environment. The overarching objective is to enhance our understanding of the fundamental mechanisms underlying these sex differences.
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Affiliation(s)
- Alexandros Popotas
- Laboratory of Pediatrics, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Translational Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Georges Jacques Casimir
- Laboratory of Pediatrics, Université Libre de Bruxelles, Brussels, Belgium
- Department of Pulmonology, Allergology and Cystic Fibrosis, Queen Fabiola Childrens University Hospital (Hôpital Universitaire des Enfants Reine Fabiola) – University Hospital of Brussels (Hôpital Universitaire de Bruxelles), Brussels, Belgium
| | - Francis Corazza
- Laboratory of Translational Research, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Immunology, Centre Hospitalier Universitaire (CHU) Brugmann, Université Libre de Bruxelles, Brussels, Belgium
| | - Nicolas Lefèvre
- Laboratory of Pediatrics, Université Libre de Bruxelles, Brussels, Belgium
- Department of Pulmonology, Allergology and Cystic Fibrosis, Queen Fabiola Childrens University Hospital (Hôpital Universitaire des Enfants Reine Fabiola) – University Hospital of Brussels (Hôpital Universitaire de Bruxelles), Brussels, Belgium
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2
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Beetler DJ, Bruno KA, Watkins MM, Xu V, Chekuri I, Giresi P, Di Florio DN, Whelan ER, Edenfield BH, Walker SA, Morales-Lara AC, Hill AR, Jain A, Auda ME, Macomb LP, Shapiro KA, Keegan KC, Wolfram J, Behfar A, Stalboerger PG, Terzic A, Farres H, Cooper LT, Fairweather D. Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2303317. [PMID: 37612820 PMCID: PMC10840864 DOI: 10.1002/smll.202303317] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/11/2023] [Indexed: 08/25/2023]
Abstract
Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.
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Affiliation(s)
- Danielle J. Beetler
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota 55902, USA
| | - Katelyn A. Bruno
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, 32608
| | - Molly M. Watkins
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota 55902, USA
| | - Vivian Xu
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Isha Chekuri
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Presley Giresi
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Damian N. Di Florio
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota 55902, USA
| | - Emily R. Whelan
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota 55902, USA
| | | | - Sierra A. Walker
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Biochemistry and Molecular Biology, Rochester, Minnesota 55902, USA
| | | | - Anneliese R. Hill
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Angita Jain
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Matthew E. Auda
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Logan P. Macomb
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Kathryn A. Shapiro
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Kevin C. Keegan
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Joy Wolfram
- School of Chemical Engineering, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Atta Behfar
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA; Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative Medicine, Rochester, MN, USA
| | - Paul G. Stalboerger
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative Medicine, Rochester, MN, USA
| | - Andre Terzic
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic Center for Regenerative Medicine, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Houssam Farres
- Department of Vascular Surgery, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - Leslie T. Cooper
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA
| | - DeLisa Fairweather
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota 55902, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida 32224, USA; Department of Immunology, Mayo Clinic, Jacksonville, Florida 32224, USA
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3
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Abstract
Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.
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Affiliation(s)
- DeLisa Fairweather
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Department of Environmental Health Sciences and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (D.F.,)
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Danielle J. Beetler
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Mayo Clinic Graduate School of Biomedical Sciences (D.J.B., D.N.D.), Mayo Clinic, Jacksonville, FL
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Damian N. Di Florio
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Mayo Clinic Graduate School of Biomedical Sciences (D.J.B., D.N.D.), Mayo Clinic, Jacksonville, FL
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Nicolas Musigk
- Deutsches Herzzentrum der Charité, Berlin, Germany (N.M., B.H.)
| | | | - Leslie T. Cooper
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
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Fairweather D, Beetler DJ, Musigk N, Heidecker B, Lyle MA, Cooper LT, Bruno KA. Sex and gender differences in myocarditis and dilated cardiomyopathy: An update. Front Cardiovasc Med 2023; 10:1129348. [PMID: 36937911 PMCID: PMC10017519 DOI: 10.3389/fcvm.2023.1129348] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/06/2023] [Indexed: 03/06/2023] Open
Abstract
In the past decade there has been a growing interest in understanding sex and gender differences in myocarditis and dilated cardiomyopathy (DCM), and the purpose of this review is to provide an update on this topic including epidemiology, pathogenesis and clinical presentation, diagnosis and management. Recently, many clinical studies have been conducted examining sex differences in myocarditis. Studies consistently report that myocarditis occurs more often in men than women with a sex ratio ranging from 1:2-4 female to male. Studies reveal that DCM also has a sex ratio of around 1:3 women to men and this is also true for familial/genetic forms of DCM. Animal models have demonstrated that DCM develops after myocarditis in susceptible mouse strains and evidence exists for this progress clinically as well. A consistent finding is that myocarditis occurs primarily in men under 50 years of age, but in women after age 50 or post-menopause. In contrast, DCM typically occurs after age 50, although the age that post-myocarditis DCM occurs has not been investigated. In a small study, more men with myocarditis presented with symptoms of chest pain while women presented with dyspnea. Men with myocarditis have been found to have higher levels of heart failure biomarkers soluble ST2, creatine kinase, myoglobin and T helper 17-associated cytokines while women develop a better regulatory immune response. Studies of the pathogenesis of disease have found that Toll-like receptor (TLR)2 and TLR4 signaling pathways play a central role in increasing inflammation during myocarditis and in promoting remodeling and fibrosis that leads to DCM, and all of these pathways are elevated in males. Management of myocarditis follows heart failure guidelines and there are currently no disease-specific therapies. Research on standard heart failure medications reveal important sex differences. Overall, many advances in our understanding of the effect of biologic sex on myocarditis and DCM have occurred over the past decade, but many gaps in our understanding remain. A better understanding of sex and gender effects are needed to develop disease-targeted and individualized medicine approaches in the future.
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Affiliation(s)
- DeLisa Fairweather
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
- Department of Environmental Health Sciences and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, United States
| | - Danielle J. Beetler
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Nicolas Musigk
- Department of Cardiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Bettina Heidecker
- Department of Cardiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Melissa A. Lyle
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Leslie T. Cooper
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
| | - Katelyn A. Bruno
- Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States
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5
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Barra NG, Kwon YH, Morrison KM, Steinberg GR, Wade MG, Khan WI, Vijayan MM, Schertzer JD, Holloway AC. Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects. Am J Physiol Endocrinol Metab 2022; 323:E80-E091. [PMID: 35575233 DOI: 10.1152/ajpendo.00049.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.
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Affiliation(s)
- Nicole G Barra
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Yun Han Kwon
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Katherine M Morrison
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Michael G Wade
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada
| | - Waliul I Khan
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Alison C Holloway
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
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6
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Zheng SY, Dong JZ. Role of Toll-Like Receptors and Th Responses in Viral Myocarditis. Front Immunol 2022; 13:843891. [PMID: 35514979 PMCID: PMC9062100 DOI: 10.3389/fimmu.2022.843891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Myocarditis is the common cause of sudden cardiac death, dilated cardiomyopathy (DCM) and heart failure (HF) in young adults. The most common type of myocarditis is viral myocarditis (VMC). Toll-like receptors (TLRs) are vital to identify pathogens in vivo. TLRs promote the differentiation of naive CD4+T cells to T helper (Th) cells, activate the immune response, and participate in the pathogenesis of autoimmune and allergic diseases. Although the pathogenesis of VMC is unclear, autoimmune responses have been confirmed to play a significant role; hence, it could be inferred that VMC is closely related to TLRs and Th responses. Some drugs have been found to improve the prognosis of VMC by regulating the immune response through activated TLRs. In this review, we discuss the role of TLRs and Th responses in VMC.
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Affiliation(s)
- Shi-Yue Zheng
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jian-Zeng Dong
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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7
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Murakami T, Komiyama T, Kobayashi H, Ikari Y. Gender Differences in Takotsubo Syndrome. BIOLOGY 2022; 11:biology11050653. [PMID: 35625378 PMCID: PMC9138502 DOI: 10.3390/biology11050653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023]
Abstract
Simple Summary The manifestation of Takotsubo Syndrome (TTS) may be different in males and females based on past reports and our clinical research. However, the gender differences in TTS are unknown because patients with TTS are predominantly female. TTS is common in females; however, approximately 10–20% of males have TTS and it has been reported that in-hospital complications mostly occur in males. TTS in males is often caused by physical stress and often develops in the hospital or during hospitalization. TTS in males is associated with severe cardiac complications, which may require careful observations and interventions. Regarding the pathogenic mechanism of TTS, it has been reported that decreased estrogen levels, common in postmenopausal females, are involved in the pathogenic mechanism. Moreover, the pathological findings and gene expression were different in males and females. From these results, it can be considered that the mechanism of the onset of TTS may be different between males and females. Abstract Most patients with Takotsubo Syndrome (TTS) are postmenopausal females. TTS in males is rare and gender differences have not been sufficiently investigated. Therefore, we investigated gender differences in TTS. TTS in males and females is often triggered by physical and emotional stress, respectively. Heart failure, a severe in-hospital complication, requires greater mechanical respiratory support in males. Fatal arrhythmias such as ventricular tachycardia and ventricular fibrillation and in-hospital mortality rates are higher in males. The white blood cell (WBC) count has been shown to be higher in males than in females with cardiovascular death compared with non-cardiovascular death. Therefore, the WBC count, a simple marker, may reflect severe TTS. Decreased estrogen levels, common in postmenopausal females, are a pathogenic mechanism of TTS. Females have a more significant increase in the extracellular matrix-receptor interaction than males. Moreover, the pathological findings after hematoxylin–eosin staining were different in males and females. Males had more severe complications than females in the acute phase of TTS; thus, more careful observations and interventions are likely required. From these results, it can be considered that the mechanism of the onset of TTS may be different between males and females. Therefore, it is necessary to fully understand the gender differences in order to more effectively manage TTS.
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Affiliation(s)
- Tsutomu Murakami
- Department of Cardiology, School of Medicine, Tokay University, Isehara 259-1193, Japan;
- Correspondence: (T.M.); (T.K.)
| | - Tomoyoshi Komiyama
- Department of Clinical Pharmacology, School of Medicine, Tokay University, Isehara 259-1193, Japan;
- Correspondence: (T.M.); (T.K.)
| | - Hiroyuki Kobayashi
- Department of Clinical Pharmacology, School of Medicine, Tokay University, Isehara 259-1193, Japan;
| | - Yuji Ikari
- Department of Cardiology, School of Medicine, Tokay University, Isehara 259-1193, Japan;
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8
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Wu L, Fiet MD, Raaijmakers DR, Woudstra L, van Rossum AC, Niessen HWM, Krijnen PAJ. Transient atrial inflammation in a murine model of Coxsackievirus B3-induced myocarditis. Int J Exp Pathol 2022; 103:149-155. [PMID: 35363404 PMCID: PMC9264345 DOI: 10.1111/iep.12438] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/21/2022] [Accepted: 03/06/2022] [Indexed: 12/02/2022] Open
Abstract
Atrial dysfunction is a relatively common complication of acute myocarditis, although its pathophysiology is unclear. There is limited information on myocarditis‐associated histological changes in the atria and how they develop in time. The aim of this study therefore was to investigate inflammation, fibrosis and viral genome in the atria in time after mild CVB3‐induced viral myocarditis (VM) in mice. C3H mice (n = 68) were infected with 105 PFU of Coxsackievirus B3 (CVB3) and were compared with uninfected mice (n = 10). Atrial tissue was obtained at days 4, 7, 10, 21, 35 or 49 post‐infection. Cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells was quantified by (immuno)histochemical staining. The CVB3 RNA was determined by in situ hybridization, and fibrosis was evaluated by elastic van Gieson (EvG) staining. In the atria of VM mice, the numbers of lymphocytes on days 4 and 7 (p < .05) and days 10 (p < .01); macrophages on days 7 (p < .01) and 10 (p < .05); neutrophils on days 4 (p < .05); and mast cells on days 4 and 7 (p < .05) increased significantly compared with control mice and decreased thereafter to basal levels. No cardiomyocyte death was observed, and the CVB3 genome was detected in only one infected mouse on Day 4 post‐infection. No significant changes in the amount of atrial fibrosis were found between VM and control mice. A temporary increase in inflammation is induced in the atria in the acute phase of CVB3‐induced mild VM, which may facilitate the development of atrial arrhythmia and contractile dysfunction.
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Affiliation(s)
- Linghe Wu
- Department of Pathology, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Mitchell D Fiet
- Department of Pathology, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Daan R Raaijmakers
- Department of Pathology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands
| | - Linde Woudstra
- Department of Reproductive Medicine, Reinier de Graaf Hospital, Voorburg, The Netherlands
| | - Albert C van Rossum
- Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.,Department of Cardiac Surgery, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.,Department of Cardiology, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
| | - Hans W M Niessen
- Department of Pathology, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.,Department of Cardiology, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
| | - Paul A J Krijnen
- Department of Pathology, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam University Medical Centers, location AMC, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
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9
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Guimarães TT, Gomes SMR, Albuquerque RAAC, Lima AKC, Braga GF, Souza JB, Assis M, Brito ACS, Santos RF, Da Silva T, Siqueira LM, Ventura BD, Rodrigues LS, Terra R, Da Silva SAG, Dutra PML. Chronic Aerobic Training at Different Volumes in the Modulation of Macrophage Function and in vivo Infection of BALB/c Mice by Leishmania major. Front Microbiol 2021; 12:734355. [PMID: 34616386 PMCID: PMC8489854 DOI: 10.3389/fmicb.2021.734355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/09/2021] [Indexed: 11/23/2022] Open
Abstract
Physical inactivity is one of the main causes of chronic diseases; however, strenuous exercise can induce immunosuppression. Several studies suggest that moderate amounts of exercise lead to a Th1 response, favoring the resolution of infections caused by intracellular microorganisms, while high volumes of exercise tend to direct the response to Th2, favoring infection by them. Leishmaniasis is a parasitic disease promoted by parasites of the Leishmania genus, with clinical manifestations that vary according to the species of the parasite and the immune response of the host. The experimental Leishmania major–BALB/C mouse model provides a good model for the resistance (Th1 response) or susceptibility (Th2 response) that determines the progression of this infection. The aim of this study was to evaluate the effect of aerobic training at different volumes on modulation of in vitro macrophage infection by L. major, as well as to assess the effect of high volume (HV) aerobic training on the development of L. major in vivo in BALB/c mice. Uninfected animals were submitted to various exercise volumes: none (SED), light (LV), moderate (MV), high (HV), very high (VHV), and tapering (TAP). The macrophages of these animals were infected by L. major and the LV and MV groups showed a decrease in the infection factor, while the VHV showed an increase in the infection factor, when treated with LPS. The cytokine concentration pattern measured in the supernatants of these macrophages suggested a predominant Th1 response profile in the LV and MV groups, while the Th2 profile predominated in the VHV and TAP groups. Groups of BALB/C mice infected with L. major were subjected to high volume (iHV) or non-periodized high volume (iNPHV) exercise or kept sedentary (iSED). The exercised animals suffered a significant increase in injuries caused by the parasites. The animals in the group submitted to high volume exercise (iHV) showed visceralization of the infection. These data strongly suggest that a very high volume of aerobic training increased the susceptibility of BALB/C mice to L. major infection, while moderate distribution of training loads promoted immunological balance, better controlling the infection by this parasite.
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Affiliation(s)
- T T Guimarães
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - S M R Gomes
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - R A A C Albuquerque
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - A K C Lima
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - G F Braga
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - J B Souza
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - M Assis
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - A C S Brito
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - R F Santos
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - T Da Silva
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - L M Siqueira
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - B D Ventura
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - L S Rodrigues
- Laboratory of Immunopathology, Faculty of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - R Terra
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.,Colégio Brigadeiro Newton Braga (CBNB), Diretoria de Ensino (DIRENS), Força Aérea Brasileira (FAB), Rio de Janeiro, Brazil
| | - S A G Da Silva
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - P M L Dutra
- Discipline of Parasitology, Department of Microbiology, Immunology and Parasitology, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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10
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Barcena ML, Jeuthe S, Niehues MH, Pozdniakova S, Haritonow N, Kühl AA, Messroghli DR, Regitz-Zagrosek V. Sex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis. Front Immunol 2021; 12:686384. [PMID: 34122450 PMCID: PMC8195335 DOI: 10.3389/fimmu.2021.686384] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022] Open
Abstract
Increasing evidence suggests male sex as a potential risk factor for a higher incidence of cardiac fibrosis, stronger cardiac inflammation, and dilated cardiomyopathy (DCM) in human myocarditis. Chronic activation of the immune response in myocarditis may trigger autoimmunity. The experimental autoimmune myocarditis (EAM) model has been well established for the study of autoimmune myocarditis, however the role of sex in this pathology has not been fully explored. In this study, we investigated sex differences in the inflammatory response in the EAM model. We analyzed the cardiac function, as well as the inflammatory stage and fibrosis formation in the heart of EAM male and female rats. 21 days after induction of EAM, male EAM rats showed a decreased ejection fraction, stroke volume and cardiac output, while females did not. A significantly elevated number of infiltrates was detected in myocardium in both sexes, indicating the activation of macrophages following EAM induction. The level of anti-inflammatory macrophages (CD68+ ArgI+) was only significantly increased in female hearts. The expression of Col3A1 and fibrosis formation were more prominent in males. Furthermore, prominent pro-inflammatory factors were increased only in male rats. These findings indicate sex-specific alterations in the inflammatory stage of EAM, with a pro-inflammatory phenotype appearing in males and an anti-inflammatory phenotype in females, which both significantly affect cardiac function in autoimmune myocarditis.
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Affiliation(s)
- Maria Luisa Barcena
- Department of Geriatrics and Medical Gerontology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Berlin Partner Site, Berlin, Germany
| | - Sarah Jeuthe
- DZHK (German Centre for Cardiovascular Research), Berlin Partner Site, Berlin, Germany.,Department of Internal Medicine - Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Maximilian H Niehues
- Department of Geriatrics and Medical Gerontology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Sofya Pozdniakova
- Department of Geriatrics and Medical Gerontology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,Climate and Health Program (CLIMA), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
| | - Natalie Haritonow
- Department of Geriatrics and Medical Gerontology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Anja A Kühl
- iPATH Berlin-Immunopathology for Experimental Models, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Daniel R Messroghli
- DZHK (German Centre for Cardiovascular Research), Berlin Partner Site, Berlin, Germany.,Department of Internal Medicine - Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.,Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vera Regitz-Zagrosek
- Institute for Gender in Medicine, Center for Cardiovascular Research, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.,Department of Cardiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
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11
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Favere K, Bosman M, Klingel K, Heymans S, Van Linthout S, Delputte PL, De Sutter J, Heidbuchel H, Guns PJ. Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis? Viruses 2021; 13:v13061003. [PMID: 34072044 PMCID: PMC8227433 DOI: 10.3390/v13061003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/30/2022] Open
Abstract
Myocarditis is an inflammatory disease of the heart with viral infections being the most common aetiology. Its complex biology remains poorly understood and its clinical management is one of the most challenging in the field of cardiology. Toll-like receptors (TLRs), a family of evolutionarily conserved pattern recognition receptors, are increasingly known to be implicated in the pathophysiology of viral myocarditis. Their central role in innate and adaptive immune responses, and in the inflammatory reaction that ensues, indeed makes them prime candidates to profoundly affect every stage of the disease process. This review describes the pathogenesis and pathophysiology of viral myocarditis, and scrutinises the role of TLRs in every phase. We conclude with directions for future research in this field.
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Affiliation(s)
- Kasper Favere
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, 2610 Antwerp, Belgium;
- Department of Cardiology, Antwerp University Hospital, 2650 Antwerp, Belgium
- Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium;
- Correspondence:
| | - Matthias Bosman
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
| | - Karin Klingel
- Cardiopathology, Institute for Pathology, University Hospital Tuebingen, 72076 Tuebingen, Germany;
| | - Stephane Heymans
- Department of Cardiology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Centre for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium
| | - Sophie Van Linthout
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH) at Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany;
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany
| | - Peter L. Delputte
- Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Antwerp, Belgium;
| | - Johan De Sutter
- Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium;
| | - Hein Heidbuchel
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, 2610 Antwerp, Belgium;
- Department of Cardiology, Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
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12
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Hanson HE, Zimmer C, Koussayer B, Schrey AW, Maddox JD, Martin LB. Epigenetic potential affects immune gene expression in house sparrows. J Exp Biol 2021; 224:224/6/jeb238451. [PMID: 33775934 DOI: 10.1242/jeb.238451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/06/2021] [Indexed: 12/15/2022]
Abstract
Epigenetic mechanisms may play a central role in mediating phenotypic plasticity, especially during range expansions, when populations face a suite of novel environmental conditions. Individuals may differ in their epigenetic potential (EP; their capacity for epigenetic modifications of gene expression), which may affect their ability to colonize new areas. One form of EP, the number of CpG sites, is higher in introduced house sparrows (Passer domesticus) than in native birds in the promoter region of a microbial surveillance gene, Toll-like Receptor 4 (TLR4), which may allow invading birds to fine-tune their immune responses to unfamiliar parasites. Here, we compared TLR4 gene expression from whole blood, liver and spleen in house sparrows with different EP, first challenging some birds with lipopolysaccharide (LPS), to increase gene expression by simulating a natural infection. We expected that high EP would predict high inducibility and reversibility of TLR4 expression in the blood of birds treated with LPS, but we did not make directional predictions regarding organs, as we could not repeatedly sample these tissues. We found that EP was predictive of TLR4 expression in all tissues. Birds with high EP expressed more TLR4 in the blood than individuals with low EP, regardless of treatment with LPS. Only females with high EP exhibited reversibility in gene expression. Further, the effect of EP varied between sexes and among tissues. Together, these data support EP as one regulator of TLR4 expression.
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Affiliation(s)
- Haley E Hanson
- University of South Florida, Global Health and Infectious Disease Research, Tampa, FL 33612, USA
| | - Cedric Zimmer
- University of South Florida, Global Health and Infectious Disease Research, Tampa, FL 33612, USA
| | - Bilal Koussayer
- University of South Florida, Global Health and Infectious Disease Research, Tampa, FL 33612, USA
| | - Aaron W Schrey
- Georgia Southern University Armstrong Campus, Department of Biology, Savannah, GA 31419, USA
| | - J Dylan Maddox
- Field Museum of Natural History, 1400 S. Lake Shore Drive, Chicago, IL 60605, USA.,American Public University System, Environmental Sciences, Charles Town, WV 25414, USA.,Universidad Científica del Perú, Laboratorio de Biotecnología y Bioenergética, Iquitos 16007, Perú
| | - Lynn B Martin
- University of South Florida, Global Health and Infectious Disease Research, Tampa, FL 33612, USA
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13
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Al-kuraishy HM, Al-Gareeb AI, Faidah H, Al-Maiahy TJ, Cruz-Martins N, Batiha GES. The Looming Effects of Estrogen in Covid-19: A Rocky Rollout. Front Nutr 2021; 8:649128. [PMID: 33816542 PMCID: PMC8012689 DOI: 10.3389/fnut.2021.649128] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/15/2021] [Indexed: 12/17/2022] Open
Abstract
In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Hani Faidah
- Microbiology, Faculty of Medicine, Umm Al Qura University, Mecca, Saudi Arabia
| | - Thabat J. Al-Maiahy
- Department of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq
| | - Natália Cruz-Martins
- Faculty of Medicine, University of Porto, Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
- Laboratory of Neuropsychophysiology, Faculty of Psychology and Education Sciences, University of Porto, Porto, Portugal
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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14
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Khaled BM, Noha ASM, Manal AAM, Engy SM. Role of Toll-Like Receptors 2 and 4 Genes Polymorphisms in Neonatal Sepsis in a Developing Country: A Pilot Study. J PEDIAT INF DIS-GER 2020. [DOI: 10.1055/s-0040-1714710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Abstract
Objective Toll-like receptors (TLR) are one of the key molecules that alert the immune system to the presence of microbial infections. This study attempts to elucidate the role of TLR2 and TLR4 polymorphisms in neonatal sepsis.
Methods A case–control study including 30 neonates with confirmed sepsis compared with 20 neonates in a control group. TLR2 and TLR24 gene polymorphisms were confirmed by polymerase chain reaction.
Results The majority of infections were attributed to gram-negative organisms (72.5%) namely Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Results also revealed that incidence of TLR polymorphism was significantly different between the sepsis and control groups (p = 0.016). The most common polymorphism was TLR2; Arg 753 Gln (16.7%). Presence of TLR polymorphism was also associated with a longer duration of therapy (a median of 10 days for cases with positive polymorphism compared with 6.5 days for negative cases; p = 0.001).
Conclusion This pilot study suggests that any polymorphisms in TLR2 and TLR4 might have a role that interferes with the innate immune response of newborn.
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Affiliation(s)
- Bedewy M. Khaled
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Abou Seada M. Noha
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Antonios A. M. Manal
- Division of Pediatric and Critical Care Medicine, Department of Pediatrics, Alexandria University, El-Shatby Hospital, Alexandria, Egypt
| | - Saleh M. Engy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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15
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Lasrado N, Reddy J. An overview of the immune mechanisms of viral myocarditis. Rev Med Virol 2020; 30:1-14. [PMID: 32720461 DOI: 10.1002/rmv.2131] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/13/2022]
Abstract
Viral myocarditis has been identified as a major cause of dilated cardiomyopathy (DCM) that can lead to heart failure. Historically, Coxsackieviruses and adenoviruses have been commonly suspected in myocarditis/DCM patients in North America and Europe. However, this notion is changing as other viruses such as Parvovirus B19 and human herpesvirus-6 are increasingly reported as causes of myocarditis in the United States, with the most recent example being the severe acute respiratory syndrome coronavirus 2, causing the Coronavirus Disease-19. The mouse model of Coxsackievirus B3 (CVB3)-induced myocarditis, which may involve mediation of autoimmunity, is routinely used in the study of immune pathogenesis of viral infections as triggers of DCM. In this review, we discuss the immune mechanisms underlying the development of viral myocarditis with an emphasis on autoimmunity in the development of post-infectious myocarditis induced with CVB3.
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Affiliation(s)
- Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
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16
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Root-Bernstein R. Synergistic Activation of Toll-Like and NOD Receptors by Complementary Antigens as Facilitators of Autoimmune Disease: Review, Model and Novel Predictions. Int J Mol Sci 2020; 21:ijms21134645. [PMID: 32629865 PMCID: PMC7369971 DOI: 10.3390/ijms21134645] [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: 05/31/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 12/29/2022] Open
Abstract
Persistent activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) in the innate immune system is one necessary driver of autoimmune disease (AD), but its mechanism remains obscure. This study compares and contrasts TLR and NOD activation profiles for four AD (autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis) and their animal models. The failure of current AD theories to explain the disparate TLR/NOD profiles in AD is reviewed and a novel model is presented that explains innate immune support of persistent chronic inflammation in terms of unique combinations of complementary AD-specific antigens stimulating synergistic TLRs and/or NODs. The potential explanatory power of the model is explored through testable, novel predictions concerning TLR- and NOD-related AD animal models and therapies.
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17
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Lundberg R, Toft MF, Metzdorff SB, Hansen CHF, Licht TR, Bahl MI, Hansen AK. Human microbiota-transplanted C57BL/6 mice and offspring display reduced establishment of key bacteria and reduced immune stimulation compared to mouse microbiota-transplantation. Sci Rep 2020; 10:7805. [PMID: 32385373 PMCID: PMC7211022 DOI: 10.1038/s41598-020-64703-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 04/20/2020] [Indexed: 02/07/2023] Open
Abstract
Transplantation of germ-free (GF) mice with microbiota from mice or humans stimulates the intestinal immune system in disparate ways. We transplanted a human microbiota into GF C57BL/6 mice and a murine C57BL/6 microbiota into GF C57BL/6 mice and Swiss-Webster (SW) mice. Mice were bred to produce an offspring generation. 56% of the Operational Taxonomic Units (OTUs) present in the human donor microbiota established in the recipient mice, whereas 81% of the C57BL/6 OTUs established in the recipient C57BL/6 and SW mice. Anti-inflammatory bacteria such as Faecalibacterium and Bifidobacterium from humans were not transferred to mice. Expression of immune-related intestinal genes was lower in human microbiota-mice and not different between parent and offspring generation. Expression of intestinal barrier-related genes was slightly higher in human microbiota-mice. Cytokines and chemokines measured in plasma were differentially present in human and mouse microbiota-mice. Minor differences in microbiota and gene expression were found between transplanted mice of different genetics. It is concluded that important immune-regulating bacteria are lost when transplanting microbiota from humans to C57BL/6 mice, and that the established human microbiota is a weak stimulator of the murine immune system. The results are important for study design considerations in microbiota transplantation studies involving immunological parameters.
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Affiliation(s)
- Randi Lundberg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark.
- Internal Research and Development, Taconic Biosciences, 4623, Lille Skensved, Denmark.
- Chr. Hansen, 2970, Hoersholm, Denmark.
| | - Martin F Toft
- Internal Research and Development, Taconic Biosciences, 4623, Lille Skensved, Denmark
- QM Diagnostics, 6534, AT Nijmegen, The Netherlands
| | - Stine B Metzdorff
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark
| | - Camilla H F Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark
| | - Tine R Licht
- National Food Institute, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
| | - Martin I Bahl
- National Food Institute, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
| | - Axel K Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark
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18
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Di Florio DN, Sin J, Coronado MJ, Atwal PS, Fairweather D. Sex differences in inflammation, redox biology, mitochondria and autoimmunity. Redox Biol 2020; 31:101482. [PMID: 32197947 PMCID: PMC7212489 DOI: 10.1016/j.redox.2020.101482] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 02/19/2020] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Autoimmune diseases are characterized by circulating antibodies and immune complexes directed against self-tissues that result in both systemic and organ-specific inflammation and pathology. Most autoimmune diseases occur more often in women than men. One exception is myocarditis, which is an inflammation of the myocardium that is typically caused by viral infections. Sex differences in the immune response and the role of the sex hormones estrogen and testosterone are well established based on animal models of autoimmune viral myocarditis as well as in mitochondrial function leading to reactive oxygen species production. RNA viruses like coxsackievirus B3, the primary cause of myocarditis in the US, activate the inflammasome through mitochondrial antiviral signaling protein located on the mitochondrial outer membrane. Toll-like receptor 4 and the inflammasome are the primary signaling pathways that increase inflammation during myocarditis, which is increased by testosterone. This review describes what is known about sex differences in inflammation, redox biology and mitochondrial function in the male-dominant autoimmune disease myocarditis and highlights gaps in the literature and future directions.
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Affiliation(s)
- Damian N Di Florio
- Center for Clinical and Translational Science, Mayo Clinic, Jacksonville, FL, USA.
| | - Jon Sin
- Cedars-Sinai Medical Center, Heart Institute, Los Angeles, CA, USA.
| | | | | | - DeLisa Fairweather
- Center for Clinical and Translational Science, Mayo Clinic, Jacksonville, FL, USA; Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA; Department of Immunology, Mayo Clinic, Jacksonville, FL, USA; Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
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19
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De Martinis M, Sirufo MM, Suppa M, Di Silvestre D, Ginaldi L. Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment. Int J Mol Sci 2020; 21:E1535. [PMID: 32102344 PMCID: PMC7073150 DOI: 10.3390/ijms21041535] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 02/20/2020] [Indexed: 12/11/2022] Open
Abstract
Allergies are rapidly worsening in recent decades, representing the most common immunological diseases. The mechanism of disorders such as asthma, rhinocongiuntivitis, urticaria, atopic dermatitis, food and drug allergies, and anaphylaxis still remain unclear and consequently treatments is mostly still symptomatic and aspecific while developments of new therapies are limited. A growing amount of data in the literature shows us how the prevalence of allergic diseases is different in both sexes and its changes over the course of life. Genes, hormones, environmental and immunological factors affect sex disparities associated with the development and control of allergic diseases, while they more rarely are considered and reported regarding their differences related to social, psychological, cultural, economic, and employment aspects. This review describes the available knowledge on the role of sex and gender in allergies in an attempt to improve the indispensable gender perspective whose potential is still underestimated while it represents a significant turning point in research and the clinic. It will offer insights to stimulate exploration of the many aspects still unknown in this relationship that could ameliorate the preventive, diagnostic, and therapeutic strategies in allergic diseases.
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Affiliation(s)
- Massimo De Martinis
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (D.D.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, Italy
| | - Maria Maddalena Sirufo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (D.D.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, Italy
| | - Mariano Suppa
- Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Daniela Di Silvestre
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (D.D.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, Italy
| | - Lia Ginaldi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (M.M.S.); (D.D.S.); (L.G.)
- Allergy and Clinical Immunology Unit, Center for the diagnosis and treatment of Osteoporosis, AUSL 04 Teramo, Italy
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20
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McDonald FB, Dempsey EM, O'Halloran KD. The impact of preterm adversity on cardiorespiratory function. Exp Physiol 2019; 105:17-43. [PMID: 31626357 DOI: 10.1113/ep087490] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/15/2019] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS What is the topic of this review? We review the influence of prematurity on the cardiorespiratory system and examine the common sequel of alterations in oxygen tension, and immune activation in preterm infants. What advances does it highlight? The review highlights neonatal animal models of intermittent hypoxia, hyperoxia and infection that contribute to our understanding of the effect of stress on neurodevelopment and cardiorespiratory homeostasis. We also focus on some of the important physiological pathways that have a modulatory role on the cardiorespiratory system in early life. ABSTRACT Preterm birth is one of the leading causes of neonatal mortality. Babies that survive early-life stress associated with immaturity have significant prevailing short- and long-term morbidities. Oxygen dysregulation in the first few days and weeks after birth is a primary concern as the cardiorespiratory system slowly adjusts to extrauterine life. Infants exposed to rapid alterations in oxygen tension, including exposures to hypoxia and hyperoxia, have altered redox balance and active immune signalling, leading to altered stress responses that impinge on neurodevelopment and cardiorespiratory homeostasis. In this review, we explore the clinical challenges posed by preterm birth, followed by an examination of the literature on animal models of oxygen dysregulation and immune activation in the context of early-life stress.
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Affiliation(s)
- Fiona B McDonald
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland
| | - Eugene M Dempsey
- Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland.,Department of Paediatrics & Child Health, School of Medicine, College of Medicine & Health, Cork University Hospital, Wilton, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland.,Irish Centre for Fetal and Neonatal Translational Research (INFANT) Research Centre, University College Cork, Cork, Ireland
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Stojić-Vukanić Z, Pilipović I, Bufan B, Stojanović M, Leposavić G. Age and sex determine CD4+ T cell stimulatory and polarizing capacity of rat splenic dendritic cells. Biogerontology 2019; 21:83-107. [PMID: 31646402 DOI: 10.1007/s10522-019-09845-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/14/2019] [Indexed: 12/21/2022]
Abstract
The study investigated influence of sex and age on splenic myeloid dendritic cells (DCs) from Dark Agouti rats. Freshly isolated DCs from young males exhibited less mature phenotype and greater endocytic capacity compared with those from age-matched females. Upon LPS stimulation in vitro they were less potent in stimulating allogeneic CD4+ cells in mixed leukocyte reaction (MLR), due to lower expression of MHC II, and greater NO and IL-10 production. In accordance with higher TGF-β production, young male rat DCs were less potent in stimulating IL-17 production in MLR than those from young females. Irrespective of sex, endocytic capacity and responsiveness of DCs to LPS stimulation in culture, judging by their allostimulatory capacity in MLR decreased with age, reflecting decline in MHC II surface density followed by their greater NO production; the effects more prominent in females. Additionally, compared with LPS-stimulated DCs from young rats, those from sex-matched aged rats were more potent in stimulating IL-10 production in MLR, whereas capacity of DCs from aged female and male rats to stimulate IL-17 production remained unaltered and decreased, respectively. This reflected age-related shift in IL-6/TGF-β production level ratio in LPS-stimulated DC cultures towards TGF-β, and sex-specific age-related remodeling CD4+ cell cytokine pathways. Additionally, compared with LPS-stimulated DCs from young rats, those cells from sex-matched aged rats were less potent in stimulating IFN-γ production in MLR, the effect particularly prominent in MLRs encompassing male rat DCs. The study showed that stimulatory and polarizing capacity of DCs depends on rat sex and age.
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Affiliation(s)
- Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, Belgrade, 11221, Serbia
| | - Ivan Pilipović
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, Belgrade, 11221, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, Belgrade, 11221, Serbia
| | - Marija Stojanović
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, Belgrade, 11221, Serbia
| | - Gordana Leposavić
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, Belgrade, 11221, Serbia.
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22
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Nguyen L, Castro O, De Dios R, Sandoval J, McKenna S, Wright CJ. Sex-differences in LPS-induced neonatal lung injury. Sci Rep 2019; 9:8514. [PMID: 31186497 PMCID: PMC6560218 DOI: 10.1038/s41598-019-44955-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 05/28/2019] [Indexed: 02/08/2023] Open
Abstract
Being of the male sex has been identified as a risk factor for multiple morbidities associated with preterm birth, including bronchopulmonary dysplasia (BPD). Exposure to inflammatory stress is a well-recognized risk factor for developing BPD. Whether there is a sex difference in pulmonary innate immune TLR4 signaling, lung injury and subsequent abnormal lung development is unknown. Neonatal (P0) male and female mice (ICR) were exposed to systemic LPS (5 mg/kg, IP) and innate immune signaling, and the transcriptional response were assessed (1 and 5 hours), along with lung development (P7). Male and female mice demonstrated a similar degree of impaired lung development with decreased radial alveolar counts, increased surface area, increased airspace area and increased mean linear intercept. We found no differences between male and female mice in the baseline pulmonary expression of key components of TLR4-NFκB signaling, or in the LPS-induced pulmonary expression of key mediators of neonatal lung injury. Finally, we found no difference in the kinetics of LPS-induced pulmonary NFκB activation between male and female mice. Together, these data support the conclusion that the innate immune response to early postnatal LPS exposure and resulting pulmonary sequelae is similar in male and female mice.
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Affiliation(s)
- Leanna Nguyen
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Odalis Castro
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Robyn De Dios
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Jeryl Sandoval
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Sarah McKenna
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
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23
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Inflammation and fibrosis in murine models of heart failure. Basic Res Cardiol 2019; 114:19. [PMID: 30887214 DOI: 10.1007/s00395-019-0722-5] [Citation(s) in RCA: 263] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 02/12/2019] [Indexed: 02/07/2023]
Abstract
Heart failure is a consequence of various cardiovascular diseases and associated with poor prognosis. Despite progress in the treatment of heart failure in the past decades, prevalence and hospitalisation rates are still increasing. Heart failure is typically associated with cardiac remodelling. Here, inflammation and fibrosis are thought to play crucial roles. During cardiac inflammation, immune cells invade the cardiac tissue and modulate tissue-damaging responses. Cardiac fibrosis, however, is characterised by an increased amount and a disrupted composition of extracellular matrix proteins. As evidence exists that cardiac inflammation and fibrosis are potentially reversible in experimental and clinical set ups, they are interesting targets for innovative heart failure treatments. In this context, animal models are important as they mimic clinical conditions of heart failure patients. The advantages of mice in this respect are short generation times and genetic modifications. As numerous murine models of heart failure exist, the selection of a proper disease model for a distinct research question is demanding. To facilitate this selection, this review aims to provide an overview about the current understanding of the pathogenesis of cardiac inflammation and fibrosis in six frequently used murine models of heart failure. Hence, it compares the models of myocardial infarction with or without reperfusion, transverse aortic constriction, chronic subjection to angiotensin II or deoxycorticosterone acetate, and coxsackievirus B3-induced viral myocarditis in this context. It furthermore provides information about the clinical relevance and the limitations of each model, and, if applicable, about the recent advancements in their methodological proceedings.
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Taneja V. Sex Hormones Determine Immune Response. Front Immunol 2018; 9:1931. [PMID: 30210492 PMCID: PMC6119719 DOI: 10.3389/fimmu.2018.01931] [Citation(s) in RCA: 355] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 08/06/2018] [Indexed: 12/19/2022] Open
Affiliation(s)
- Veena Taneja
- Department of Immunology and Rheumatology, Mayo Clinic, Rochester, MN, United States
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25
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Chamekh M, Deny M, Romano M, Lefèvre N, Corazza F, Duchateau J, Casimir G. Differential Susceptibility to Infectious Respiratory Diseases between Males and Females Linked to Sex-Specific Innate Immune Inflammatory Response. Front Immunol 2017; 8:1806. [PMID: 29321783 PMCID: PMC5733536 DOI: 10.3389/fimmu.2017.01806] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/30/2017] [Indexed: 11/13/2022] Open
Abstract
It is widely acknowledged that males and females exhibit contrasting degrees of susceptibility to infectious and non-infectious inflammatory diseases. This is particularly observed in respiratory diseases where human males are more likely to be affected by infection-induced acute inflammations compared to females. The type and magnitude of the innate immune inflammatory response play a cardinal role in this sex bias. Animal models mimicking human respiratory diseases have been used to address the biological factors that could explain the distinct outcomes. In this review, we focus on our current knowledge about experimental studies investigating sex-specific differences in infection-induced respiratory diseases and we provide an update on the most important innate immune mechanisms that could explain sex bias of the inflammatory response. We also discuss whether conclusions drawn from animal studies could be relevant to human.
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Affiliation(s)
- Mustapha Chamekh
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Queen Fabiola University Children's Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Maud Deny
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Queen Fabiola University Children's Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Marta Romano
- Service of Immunology, Scientific Institute for Public Health (WIV-ISP), Brussels, Belgium
| | - Nicolas Lefèvre
- Laboratory of Translational Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.,Department of Pulmonology, Allergology and Cystic Fibrosis, Queen Fabiola University Children's Hospital, Brussels, Belgium
| | - Francis Corazza
- Laboratory of Translational Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Jean Duchateau
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Queen Fabiola University Children's Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Georges Casimir
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Queen Fabiola University Children's Hospital, Université Libre de Bruxelles, Brussels, Belgium.,Department of Pulmonology, Allergology and Cystic Fibrosis, Queen Fabiola University Children's Hospital, Brussels, Belgium
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26
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Koenig A, Buskiewicz I, Huber SA. Age-Associated Changes in Estrogen Receptor Ratios Correlate with Increased Female Susceptibility to Coxsackievirus B3-Induced Myocarditis. Front Immunol 2017; 8:1585. [PMID: 29201031 PMCID: PMC5696718 DOI: 10.3389/fimmu.2017.01585] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/03/2017] [Indexed: 01/01/2023] Open
Abstract
Sexual bias is a hallmark in various diseases. This review evaluates sexual dimorphism in clinical and experimental coxsackievirus B3 (CVB3) myocarditis, and how sex bias in the experimental disease changes with increased age. Coxsackieviruses are major causes of viral myocarditis, an inflammation of the heart muscle, which is more frequent and severe in men than women. Young male mice infected with CVB3 develop heart-specific autoimmunity and severe myocarditis. Females infected during estrus (high estradiol) develop T-regulatory cells and when infected during diestrus (low estradiol) develop autoimmunity similar to males. During estrus, protection depends on estrogen receptor alpha (ERα), which promotes type I interferon, activation of natural killer/natural killer T cells and suppressor cell responses. Estrogen receptor beta has opposing effects to ERα and supports pro-inflammatory immunity. However, the sexual dimorphism of the disease is significantly ameliorated in aged animals when old females become as susceptible as males. This correlates to a selective loss of the ERα that is required for immunosuppression. Therefore, sex-associated hormones control susceptibility in the virus-mediated disease, but their impact can alter with the age and physiological stage of the individual.
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Affiliation(s)
- Andreas Koenig
- Department of Pathology, University of Vermont, Burlington, VT, United States
| | - Iwona Buskiewicz
- Department of Pathology, University of Vermont, Burlington, VT, United States
| | - Sally A Huber
- Department of Pathology, University of Vermont, Burlington, VT, United States
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27
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DeWolf SE, Shigeoka AA, Scheinok A, Kasimsetty SG, Welch AK, McKay DB. Expression of TLR2, NOD1, and NOD2 and the NLRP3 Inflammasome in Renal Tubular Epithelial Cells of Male versus Female Mice. Nephron Clin Pract 2017; 137:68-76. [PMID: 28614830 DOI: 10.1159/000456016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/03/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gender-biased outcomes are associated with acute kidney injury (AKI) and human and animal studies have shown that females are preferentially protected from renal ischemia. However, the reason for this is not known. One clue might lie with pattern recognition receptors (PRRs), which are triggers of ischemic injury when ligated by molecules in the ischemic milieu. Several PRR families are expressed by renal tubular epithelial cells (RTEs) and incite cell death signaling and production of pro-inflammatory molecules. Blockade of specific PRRs (e.g., TLR2, NOD1, NOD2, and NLRP3) provides highly significant protection from ischemic RTE injury. As a first step to understand gender-biased outcomes of AKI, we tested whether constitutive gender-based differences exist in expression of these PRRS in RTEs. METHODS To determine whether PRR expression differences exist, primary RTEs isolated from male and female WT kidneys were examined by FACS, qPCR, and Western Blot for expression of TLR2, NOD1, NOD2, and NLRP3 inflammasome components. RESULTS No RTE gender-based differences in TLR2, NOD1, NOD2, NLRP3, or ASC were found. RTEs from female kidneys had approximately half the mRNA, but the same protein concentration of pro-caspase-1 compared to RTEs isolated from male kidneys. CONCLUSIONS Our findings indicate that intrinsic gender differences in RTE expression of TLR2, NOD1, NOD2, NLRP3, and ASC are not responsible for the gender-biased outcomes observed in ischemia/reperfusion injury. The lower caspase-1 mRNA expression in RTEs from females warrants further exploration of additional upstream signals that might differentially regulate caspase-1 in male vs. female RTEs.
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Affiliation(s)
- Sean E DeWolf
- Division of Nephrology/Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA, USA
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Das D, Sarkar N, Sengupta I, Pal A, Saha D, Bandopadhyay M, Das C, Narayan J, Singh SP, Chakravarty R. Anti-viral role of toll like receptor 4 in hepatitis B virus infection: An in vitro study. World J Gastroenterol 2016; 22:10341-10352. [PMID: 28058014 PMCID: PMC5175246 DOI: 10.3748/wjg.v22.i47.10341] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 10/01/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM Toll like receptors plays a significant anti-viral role in different infections. The aim of this study was to look into the role of toll like receptor 4 (TLR4) in hepatitis B virus (HBV) infection.
METHODS Real time PCR was used to analyze the transcription of TLR4 signaling molecules, cell cycle regulators and HBV DNA viral load after triggering the HepG2.2.15 cells with TLR4 specific ligand. Nuclear factor (NF)-κB translocation on TLR4 activation was analyzed using microscopic techniques. Protein and cell cycle analysis was done using Western Blot and FACS respectively.
RESULTS The present study shows that TLR4 activation represses HBV infection. As a result of HBV suppression, there are several changes in host factors which include partial release in G1/S cell cycle arrest and changes in host epigenetic marks. Finally, it was observed that anti-viral action of TLR4 takes place through the NF-κB pathway.
CONCLUSION The study shows that TLR4 activation in HBV infection brings about changes in hepatocyte microenvironment and can be used for developing a promising therapeutic target in future.
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29
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Kuo SM. Gender Difference in Bacteria Endotoxin-Induced Inflammatory and Anorexic Responses. PLoS One 2016; 11:e0162971. [PMID: 27631979 PMCID: PMC5025071 DOI: 10.1371/journal.pone.0162971] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 08/31/2016] [Indexed: 02/07/2023] Open
Abstract
Inflammation-related anorexic response has been observed in systemic diseases as well as in localized infection and is an important issue in patient care. We tested the hypothesis that upon the same endotoxin exposure, males have more severe inflammatory responses and thus suffer from more negative effect on appetite. Ten-week old male and female mice were compared in their plasma levels of pro-inflammatory cytokines after a body weight-based i.p. injection of bacterial endotoxin lipopolysaccharide. Male mice consistently showed significantly higher levels of IL6 and TNFα than female mice. The difference was observed starting at 3 hours after the systemic endotoxin exposure. It was independent of the level of endotoxin dosage and of the genotype of the anti-inflammatory cytokine, IL10. Interestingly, endotoxin-injected male mice also had significantly higher plasma IL10 levels compared to the female mice. Pre-puberty young mice showed no gender differences in the plasma levels of IL6, TNFα and IL10. Their cytokine levels were mostly between that of the adult males and females. Consistent with the higher inflammatory response in male mice, the endotoxin exposure also led to significantly more appetite loss in male mice at a range of doses in two strains of mice. Saline injection in the absence of endotoxin affected neither the cytokine levels nor the appetite. Although a direct mechanistic link between inflammation parameters and appetite was not addressed here, the results support that male gender could be a risk factor for higher pro-inflammatory cytokines and anorexic response after the endotoxin exposure.
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Affiliation(s)
- Shiu-Ming Kuo
- Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, New York, United States of America
- * E-mail:
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30
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Abstract
Viral myocarditis remains a prominent infectious-inflammatory disease for patients throughout the lifespan. The condition presents several challenges including varied modes of clinical presentation, a range of timepoints when patients come to attention, a diversity of approaches to diagnosis, a spectrum of clinical courses, and unsettled perspectives on therapeutics in different patient settings and in the face of different viral pathogens. In this review, we examine current knowledge about viral heart disease and especially provide information on evolving understanding of mechanisms of disease and efforts by investigators to identify and evaluate potential therapeutic avenues for intervention.
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Affiliation(s)
- Gabriel Fung
- From the Department of Pathology and Laboratory Medicine (G.F., H.L., Y.Q., D.Y., B.M.), Centre for Heart Lung Innovation (G.F., H.L., Y.Q., D.Y., B.M.), Centre of Excellence for Prevention of Organ Failure (PROOF Centre), and Institute for Heart + Lung Health, St. Paul's Hospital (B.M.), University of British Columbia, Vancouver, British Columbia, Canada
| | - Honglin Luo
- From the Department of Pathology and Laboratory Medicine (G.F., H.L., Y.Q., D.Y., B.M.), Centre for Heart Lung Innovation (G.F., H.L., Y.Q., D.Y., B.M.), Centre of Excellence for Prevention of Organ Failure (PROOF Centre), and Institute for Heart + Lung Health, St. Paul's Hospital (B.M.), University of British Columbia, Vancouver, British Columbia, Canada
| | - Ye Qiu
- From the Department of Pathology and Laboratory Medicine (G.F., H.L., Y.Q., D.Y., B.M.), Centre for Heart Lung Innovation (G.F., H.L., Y.Q., D.Y., B.M.), Centre of Excellence for Prevention of Organ Failure (PROOF Centre), and Institute for Heart + Lung Health, St. Paul's Hospital (B.M.), University of British Columbia, Vancouver, British Columbia, Canada
| | - Decheng Yang
- From the Department of Pathology and Laboratory Medicine (G.F., H.L., Y.Q., D.Y., B.M.), Centre for Heart Lung Innovation (G.F., H.L., Y.Q., D.Y., B.M.), Centre of Excellence for Prevention of Organ Failure (PROOF Centre), and Institute for Heart + Lung Health, St. Paul's Hospital (B.M.), University of British Columbia, Vancouver, British Columbia, Canada
| | - Bruce McManus
- From the Department of Pathology and Laboratory Medicine (G.F., H.L., Y.Q., D.Y., B.M.), Centre for Heart Lung Innovation (G.F., H.L., Y.Q., D.Y., B.M.), Centre of Excellence for Prevention of Organ Failure (PROOF Centre), and Institute for Heart + Lung Health, St. Paul's Hospital (B.M.), University of British Columbia, Vancouver, British Columbia, Canada.
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Gender Differences in Patients with Takotsubo Cardiomyopathy: Multi-Center Registry from Tokyo CCU Network. PLoS One 2015; 10:e0136655. [PMID: 26317750 PMCID: PMC4552760 DOI: 10.1371/journal.pone.0136655] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 08/06/2015] [Indexed: 12/17/2022] Open
Abstract
Background The clinical features of gender differences in takotsubo cardiomyopathy (TC) remain to be determined. The aim of this study was to evaluate the differences in clinical characteristics of male and female patients with TC. Methods We obtained the clinical information of 368 patients diagnosed with TC (84 male, 284 female) from the Tokyo CCU Network database collected from 1 January 2010 to 31 December 2012; the Network is comprised of 71 cardiovascular centers in the Tokyo (Japan) metropolitan area. We attempted to characterize clinical differences during hospitalization, comparing male and female patients with TC. Results There were no significant differences in apical ballooning type, median echocardiography ejection fraction, serious ventricular arrhythmias (such as ventricular tachycardia or fibrillation), or cardiovascular death between male and female patients. Male patients were younger than female patients (median age at hospitalization for male patients was 72 years vs. 76 years for female patients; p = 0.040). Prior physical stress was more common in male than female patients (50.0% vs.31.3%; p = 0.002), while emotional stress was more common in female patients (19.0% vs. 31.0%; p = 0.039). Severe pump failure (defined as Killip Class > III) (20.2% vs. 10.6%; p = 0.020) and cardiopulmonary supportive therapies (28.6% vs. 12.7%, p < 0.001) were more common in male than female patients. Multivariate analysis revealed that male gender (odds ratio = 4.32, 95% CI = 1.41–13.6, p = 0.011) was an independent predictor of adverse composite cardiac events, including cardiovascular death, severe pump failure, and serious ventricular arrhythmia. Conclusions Cardiac complications in our dataset appeared to be more common in male than female patients with TC during their hospitalization. Further investigation is required to clarify the underlying mechanisms responsible for the observed gender differences.
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Meng W, Deshmukh HA, Donnelly LA, Torrance N, Colhoun HM, Palmer CNA, Smith BH. A Genome-wide Association Study Provides Evidence of Sex-specific Involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) With Diabetic Neuropathic Pain. EBioMedicine 2015; 2:1386-93. [PMID: 26629533 PMCID: PMC4634194 DOI: 10.1016/j.ebiom.2015.08.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 07/30/2015] [Accepted: 08/01/2015] [Indexed: 12/23/2022] Open
Abstract
Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. Controls were diabetic individuals who were not prescribed any of these drugs, nor amitriptyline, carbamazepine, or nortriptyline. Overall, 961 diabetic neuropathic pain cases and 3260 diabetic controls in the Genetics of Diabetes Audit and Research Tayside (GoDARTS) cohort were identified. We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74 × 10(- 7) at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02 × 10(- 7) at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research.
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Affiliation(s)
- Weihua Meng
- Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD2 4BF, UK
| | - Harshal A Deshmukh
- Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD2 4BF, UK
| | - Louise A Donnelly
- Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD1 9SY, UK
| | | | | | - Nicola Torrance
- Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD2 4BF, UK
| | - Helen M Colhoun
- Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD2 4BF, UK
| | - Colin N A Palmer
- Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD1 9SY, UK
| | - Blair H Smith
- Division of Population Health Sciences, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee DD2 4BF, UK
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Cai Z, Shen L, Ma H, Yang J, Yang D, Chen H, Wei J, Lu Q, Wang DW, Xiang M, Wang J. Involvement of Endoplasmic Reticulum Stress-Mediated C/EBP Homologous Protein Activation in Coxsackievirus B3-Induced Acute Viral Myocarditis. Circ Heart Fail 2015; 8:809-18. [PMID: 25985795 DOI: 10.1161/circheartfailure.114.001244] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 05/07/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study tested the hypothesis whether endoplasmic reticulum (ER) stress/C/EBP homologous protein (CHOP) signaling is linked with coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC) in vivo. METHODS AND RESULTS AVMC was induced by intraperitoneal injection of 1000 tissue culture infectious dose (TCID50) of CVB3 virus in mice. In AVMC mouse hearts (n=11), ER stress and CHOP were significantly activated, and were linked to the induction of proapoptotic signaling including reduction of Bcl-2, activation of Bax and caspase 3, compared with the controls (n=10), whereas these could be markedly blocked by ER stress inhibitor tauroursodeoxycholic acid administration (n=11). Moreover, chemical inhibition of ER stress significantly attenuated cardiomyocytes apoptosis, and prevented cardiac troponin I elevation, ameliorated cardiac dysfunction assessed by both hemodynamic and echocardiographic analysis, reduced viral replication, and increased survival rate after CVB3 inoculation. We further discovered that genetic ablation of CHOP (n=10) suppressed cardiac Bcl-2/Bax ratio reduction and caspase 3 activation, and prevented cardiomyotes apoptosis in vivo, compared with wild-type receiving CVB3 inoculation (n=10). Strikingly, CHOP deficiency exhibited dramatic protective effects on cardiac damage, cardiac dysfunction, viral replication, and promoted survival in CVB3-caused AVMC. CONCLUSIONS Our data imply the involvement of ER stress/CHOP signaling in CVB3-induced AVMC via proapoptotic pathways, and provide a novel strategy for AVMC treatment.
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Affiliation(s)
- Zhejun Cai
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Li Shen
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Hong Ma
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Jin Yang
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Du Yang
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Han Chen
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Jia Wei
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Qiulun Lu
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Dao Wen Wang
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.)
| | - Meixiang Xiang
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.).
| | - Jian'an Wang
- From the Key Laboratory of Cardiovascular Disease of Zhejiang Province and Department of Cardiology, Second Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China (Z.C., L.S., H.M., D.Y., H.C., M.X., J. Wang); Department of Medicine, Blood Center of Zhejiang Province, Hangzhou, China (J.Y.); Transform Medical Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China (J.Y.); Department of Pediatric Surgery (J. Wei) and Institute of Hypertension and Department of Internal Medicine (D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.L.).
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Zha X, Yue Y, Dong N, Xiong S. Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway. Can J Cardiol 2015; 31:1032-40. [PMID: 26111668 DOI: 10.1016/j.cjca.2015.03.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Revised: 02/20/2015] [Accepted: 03/03/2015] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Viral myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in viral myocarditis remains unsolved. METHODS We investigated the influence of ER stress in coxsackievirus B3 (CVB3)-induced viral myocarditis by dynamically detecting its activation in CVB3-infected hearts, analyzing its association with myocarditis severity, and exploring its impact on disease development by modulating the strength of ER stress with the chemical activator tunicamycin (Tm) or the inhibitor tauroursodeoxycholic acid (TUDCA). The underlying signal pathway of ER stress in CVB3-induced myocarditis was also deciphered. RESULTS We found that myocardial expression of Grp78 and Grp94, 2 ER stress markers, was significantly increased after CVB3 infection and positively correlated with myocarditis severity. Consistently, Tm-augmented ER stress obviously aggravated myocarditis, as shown by more severe myocardial inflammation, reduced cardiac function, and a lower survival rate, whereas TUDCA decreased ER stress and obviously alleviated myocarditis. This pathologic effect of ER stress could be attributed to increased levels of proinflammatory cytokine (interleukin [IL]-6, IL-12, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1) production through the IRE1-associated nuclear factor-κB (NF-kB) pathway. CONCLUSIONS ER stress accentuated CVB3-induced myocardial inflammation through the IRE1-associated NF-κB pathway. This study may help us understand the role of ER stress in viral myocarditis and promote the development of corresponding therapeutic strategies based on manipulating ER stress.
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Affiliation(s)
- Xi Zha
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
| | - Yan Yue
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
| | - Ning Dong
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
| | - Sidong Xiong
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China.
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35
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Unresolved issues in theories of autoimmune disease using myocarditis as a framework. J Theor Biol 2014; 375:101-123. [PMID: 25484004 DOI: 10.1016/j.jtbi.2014.11.022] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 11/10/2014] [Accepted: 11/20/2014] [Indexed: 11/20/2022]
Abstract
Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related.
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36
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Liu L, Yue Y, Xiong S. NK-derived IFN-γ/IL-4 triggers the sexually disparate polarization of macrophages in CVB3-induced myocarditis. J Mol Cell Cardiol 2014; 76:15-25. [PMID: 25123338 DOI: 10.1016/j.yjmcc.2014.07.021] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 07/15/2014] [Accepted: 07/28/2014] [Indexed: 10/24/2022]
Abstract
Coxsackievirus B3 (CVB3) is a common etiology of myocarditis with an increased morbidity and mortality in males. We previously reported that differential polarization of macrophages contributed to sexually dimorphic susceptibility of mice to CVB3-induced myocarditis. However, the underlying kinetics, impetus as well as the molecular mechanism remain unclear. Here, we demonstrated that myocardial macrophages started to polarize at as early as day 5 post CVB3 infection in both genders of BALB/c mice, with M1 phenotype detected in males and M2a phenotype in females, and this trend was further amplified at day 7 when myocarditis reached peak. In addition, we identified that prevailed IFN-γ in males and dominant IL-4 in females were critical myocardial cytokines for the disparate macrophage polarization, which respectively activated JAK1-STAT1 and JAK3-STAT6 pathways. Strikingly, we found that the main source of IFN-γ and IL-4 cytokines in both genders were myocardial infiltrating NK cells, which differentially secreted cytokines in various microenvironments manifested synergistically by sex hormones and CVB3 infection. Consistently, depletion of NK cells significantly impeded the myocardial macrophage polarization in both genders of CVB3-infected mice. Collectively, these data indicated that myocardial NK-derived IFN-γ/IL-4 was critical for the differential polarization of macrophages in CVB3-induced myocarditis via activating JAK1-STAT1 and JAK3-STAT6 pathways respectively. Our study may help understand the mechanism of sexually differential polarization of macrophages and provide clues for the gender bias in CVB3-induced myocarditis.
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Affiliation(s)
- Li Liu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Yan Yue
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China
| | - Sidong Xiong
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou 215123, People's Republic of China.
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37
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TLR3 plays significant roles against hepatitis B virus. Mol Biol Rep 2014; 41:3279-86. [DOI: 10.1007/s11033-014-3190-x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 01/21/2014] [Indexed: 01/30/2023]
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38
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The role of sex differences in autophagy in the heart during coxsackievirus B3-induced myocarditis. J Cardiovasc Transl Res 2013; 7:182-91. [PMID: 24323874 DOI: 10.1007/s12265-013-9525-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 11/20/2013] [Indexed: 12/28/2022]
Abstract
Under normal conditions, autophagy maintains cardiomyocyte health and integrity through turnover of organelles. During stress, oxygen and nutrient deprivation, or microbial infection, autophagy prolongs cardiomyocyte survival. Sex differences in induction of cell death may to some extent explain the disparity between the sexes in many human diseases. However, sex differences in gene expression, which regulate cell death and autophagy, were so far not taken in consideration to explain the sex bias of viral myocarditis. Coxsackievirus B3 (CVB3)-induced myocarditis is a sex-biased disease, with females being substantially less susceptible than males and sex hormones largely determine this bias. CVB3 was shown to induce and subvert the autophagosome for its optimal viral RNA replication. Gene expression analysis on mouse and human, healthy and CVB3-infected, cardiac samples of both sexes, suggests sex differences in autophagy-related gene expression. This review discusses the aspects of sex bias in autophagy induction in cardiomyocytes.
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39
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Sex differences in opisthorchiosis and the development of cholangiocarcinoma in Syrian hamster model. Parasitol Res 2013; 113:829-35. [PMID: 24318666 DOI: 10.1007/s00436-013-3713-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 11/19/2013] [Indexed: 12/20/2022]
Abstract
Worldwide, the highest incidence of cholangiocarcinoma (CCA) is found in northeast Thailand, the endemic area of Opisthorchis viverrini infection. Cumulated clinical data revealed that the majority of CCA patients are men. However, many other types of cancers are more commonly found in women. In this study, we investigated the sex differences in the development of CCA, induced by O. viverrini infection and N-nitrosodimethylamine administration, in Syrian hamsters. Histopathology, liver function tests, and fecal egg counts were analyzed. The results showed that there are no sex differences in hamsters responses to O. viverrini infection and no prevalence of CCA development. Even though serum ALT level in O. viverrini-infected or CCA hamsters was significantly increased in female compared to male (p < 0.05) and uninfected control (p < 0.05), our results may imply that the higher prevalence of opisthorchiasis and CCA in men than in women in northeast Thailand may depend on behaviors of an individual exposed to risk factors rather than gender difference.
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40
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Antoniak S, Mackman N. Coagulation, protease-activated receptors, and viral myocarditis. J Cardiovasc Transl Res 2013; 7:203-11. [PMID: 24203054 DOI: 10.1007/s12265-013-9515-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 10/16/2013] [Indexed: 12/29/2022]
Abstract
The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs). These receptors allow cells to sense changes in the extracellular environment, such as infection. Viruses activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium. Virus infection of the heart can cause myocarditis, cardiac remodeling, and heart failure. A recent study using a mouse model have shown that tissue factor, thrombin, and PAR-1 signaling all positively regulate the innate immune during viral myocarditis. In contrast, PAR-2 signaling was found to inhibit interferon-β expression and the innate immune response. These observations suggest that anticoagulants may impair the innate immune response to viral infection and that inhibition of PAR-2 may be a new strategy to reduce viral myocarditis.
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Affiliation(s)
- Silvio Antoniak
- Division of Hematology and Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, 98 Manning Drive, Campus Box 7035, Chapel Hill, NC, 27599, USA,
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41
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Casimir GJ, Lefèvre N, Corazza F, Duchateau J. Sex and inflammation in respiratory diseases: a clinical viewpoint. Biol Sex Differ 2013; 4:16. [PMID: 24128344 PMCID: PMC3765878 DOI: 10.1186/2042-6410-4-16] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 08/07/2013] [Indexed: 12/15/2022] Open
Abstract
This review discusses sex differences in the prognosis of acute or chronic inflammatory diseases. The consequences of severe inflammation vary in relation to sex, depending on illness duration. In the majority of acute diseases, males present higher mortality rates, whereas continuous chronic inflammation associated with tissue damage is more deleterious in females. The recruitment of cells, along with its clinical expression, is more significant in females, as reflected by higher inflammatory markers. Given that estrogens or androgens are known to modulate inflammation, their different levels in males and females cannot account for the sexual dimorphism observed in humans and animals from birth to death with regard to inflammation. Numerous studies evaluated receptors, cytokine production, and clinical outcomes in both animals and humans, revealing that estrogens clearly modulate the immune response, but the results are contradictory and difficult to link to hormone concentrations. Even in prepubescent children, the presentation of acute pneumonia or chronic diseases mimics the adult pattern. Several genes located on the X chromosome have been shown to encode molecules involved in inflammation. Moreover, 10% to 15% of the genes from silenced X chromosome may escape inhibition. Females are also a mosaic of cells with genes from either paternal or maternal X chromosome. Therefore, polymorphism of X-linked genes would result in the presence of two cell populations with distinct regulatory arsenals, providing females with greater diversity to fight against infectious challenges, in comparison with the uniform cell populations in hemizygous males. The similarities observed between males and Turner syndrome patients using an endotoxin stimulation model support the difference in gene expression between monosomy and disomy for the X chromosome. Considering the enhanced inflammation in females, cytokine production may be assumed to be higher in females than males. Even if all results are not clear-cut, nonetheless, many studies have reported higher cytokine levels in both male humans and animals than in females. High IL-6 levels in males correlated with poorer prognosis and shorter longevity. A sound understanding of the basic regulatory mechanisms responsible for these gender differences may lead to new therapeutic targets.
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Affiliation(s)
- Georges J Casimir
- Department of Pulmonology, Allergology and Cystic Fibrosis, Hôpital Universitaire des Enfants Reine Fabiola, Avenue JJ. Crocq 15, B-1020, Brussels, Belgium ; Laboratory of Pediatrics, Université Libre de Bruxelles (ULB), Place Arthur Van Gehuchten 4, B-1020, Brussels, Belgium
| | - Nicolas Lefèvre
- Department of Pulmonology, Allergology and Cystic Fibrosis, Hôpital Universitaire des Enfants Reine Fabiola, Avenue JJ. Crocq 15, B-1020, Brussels, Belgium ; Laboratory of Immunology, Hôpital Universitaire Brugmann, Place Arthur Van Gehuchten, 4, B-1020, Brussels, Belgium
| | - Francis Corazza
- Laboratory of Immunology, Hôpital Universitaire Brugmann, Place Arthur Van Gehuchten, 4, B-1020, Brussels, Belgium
| | - Jean Duchateau
- Laboratory of Pediatrics, Université Libre de Bruxelles (ULB), Place Arthur Van Gehuchten 4, B-1020, Brussels, Belgium
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42
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Beenakker KGM, Westendorp RGJ, Craen AJM, Slagboom PE, Heemst D, Maier AB. Pro-inflammatory capacity of classically activated monocytes relates positively to muscle mass and strength. Aging Cell 2013; 12:682-9. [PMID: 23621451 DOI: 10.1111/acel.12095] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2013] [Indexed: 12/15/2022] Open
Abstract
In mice, monocytes that exhibit a pro-inflammatory profile enter muscle tissue after muscle injury and are crucial for clearance of necrotic tissue and stimulation of muscle progenitor cell proliferation and differentiation. The aim of this study was to test if pro-inflammatory capacity of classically activated (M1) monocytes relates to muscle mass and strength in humans. This study included 191 male and 195 female subjects (mean age 64.2 years (SD 6.4) and 61.9 ± 6.4, respectively) of the Leiden Longevity Study. Pro-inflammatory capacity of M1 monocytes was assessed by ex vivo stimulation of whole blood with Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS) and TLR-2/1 agonist tripalmitoyl-S-glycerylcysteine (Pam₃Cys-SK₄), both M1 phenotype activators. Cytokines that stimulate M1 monocyte response (IFN-γ and GM-CSF) as well as cytokines that are secreted by M1 monocytes (IL-6, TNF-α, IL-12, and IL-1β) were measured. Analyses were adjusted for age, height, and body fat mass. Upon stimulation with LPS, the cytokine production capacity of INF-γ, GM-CSF, and TNF-α was significantly positively associated with lean body mass, appendicular lean mass and handgrip strength in men, but not in women. Upon stimulation with Pam₃Cys-SK₄, IL-6; TNF-α; and Il-1β were significantly positively associated with lean body mass and appendicular lean in women, but not in men. Taken together, this study shows that higher pro-inflammatory capacity of M1 monocytes upon stimulation is associated with muscle characteristics and sex dependent.
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Affiliation(s)
- Karel G. M. Beenakker
- Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
| | - Rudi G. J. Westendorp
- Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
- Netherlands Consortium for Healthy Ageing Leiden the Netherlands
| | - Anton J. M. Craen
- Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
- Netherlands Consortium for Healthy Ageing Leiden the Netherlands
| | - Pieternella E. Slagboom
- Netherlands Consortium for Healthy Ageing Leiden the Netherlands
- Department of Medical Statistics Molecular Epidemiology Leiden University Medical Center Leiden the Netherlands
| | - Diana Heemst
- Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
- Netherlands Consortium for Healthy Ageing Leiden the Netherlands
| | - Andrea B. Maier
- Department of Gerontology and Geriatrics Leiden University Medical Center Leiden the Netherlands
- Department of Internal Medicine section of gerontology and geriatrics VU University Medical Center Amsterdam the Netherlands
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