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Cutting Edge: Cross-Regulation by TLR4 and T cell Ig Mucin-3 Determines Sex Differences in Inflammatory Heart Disease
Open accessAbstract
Recent clinical studies have reinforced the importance of sex-related differences in the pathogenesis of cardiovascular diseases, with an increased incidence and mortality in men. Similar to humans, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammation in the heart even though viral replication is no greater than in females. We show that TLR4 and IFN-γ levels are significantly elevated and regulatory T cell (Treg) populations significantly reduced in the heart of males following CVB3 infection, whereas females have significantly increased T cell Ig mucin (Tim)-3, IL-4 and Treg. Blocking Tim-3 in males significantly increases inflammation and TLR4 expression while reducing Treg. In contrast, defective TLR4 signaling significantly reduces inflammation while increasing Tim-3 expression. Cross-regulation of TLR4 and Tim-3 occurs during the innate and adaptive immune response. This novel mechanism may help explain why inflammatory heart disease is more severe in males.
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“Tim-3 (T-cell immunoglobulin mucin domain 3) is a receptor that is upregulated on mast cells and macrophages after viral infection that inhibits T-cell responses and is associated with increased IL-10 release from alternatively activated macrophages. 124,125,146”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“Few females progress to DCM in humans or autoimmune/viral myocarditis animal models. 64,124”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“We showed that mast cells are the first APCs to respond to CVB3 within 15 minutes of intraperitoneal infection during autoimmune CVB3 myocarditis, leading to upregulation of TLR4, and that this response leads to rapid increases in TNF, IL-1 β , IL-6, and IFN γ in many organs including the heart. 124,146,160”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“with men developing more scar tissue and dilated cardiomyopathy (DCM) than women. 64,124,131”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“And men have more neutrophils and monocytes, whereas women have more T cells, 13,121-123 similar to autoimmune myocarditis. 124,125”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“Another key pathway upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3only models is the TLR4, caspase-1, and NLRP3 pathways that increase IL-1 β and IL-18 levels in the heart. 124,146,152,156,161-164”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“The majority of immune cells in the heart during acute myocarditis in EAM, the autoimmune CVB3 myocarditis model, and humans are CD11b+ cells that include neutrophils, macrophages, mast cells, and some dendritic cells. 124,146,152,159”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“Importantly, elevated TLR4 and IL-1 β are found on CD11b/CR3-expressing macrophages and mast cells during the innate immune response in the spleen and heart and in the heart during acute myocarditis. 124,146”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“Type I and II IFNs are a dominant immune response in CVB3 myocarditis models (and EAM) where inhibition of these pathways leads to increased viral replication, pericardial and myocardial inflammation, and DCM. 124,128,152,169,170”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“An important regulator of T cells following TLR4 activation is Tim-3, which displays sex differences during CVB3 myocarditis. 124,125,146”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“This time course is the same as is observed with the autoimmune CVB3 and murine cytomegalovirus models of myocarditis and EAM (Table S1). 35,124,170,188”
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“The accuracy of cMRI depends on the amount of scar tissue present”
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Current treatment options in (peri)myocarditis and inflammatory cardiomyopathy
Maisch, B., & Pankuweit, S. (2012) · Herz · doi:10.1007/s00059-012-3679-9 · Cited by 81
TRIF Is a Critical Survival Factor in Viral Cardiomyopathy
Riad, A., Westermann, D., Zietsch, C., Savvatis, K., Becher, P. M., Bereswill, S., Heimesaat, M. M., Lettau, O., Laßner, D., Dörner, A., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002029 · Cited by 80
Unresolved issues in theories of autoimmune disease using myocarditis as a framework
Root-Bernstein, R. S., & Fairweather, D. (2014) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2014.11.022 · Cited by 77
Self-citationTIM-3: A Novel Regulatory Molecule of Alloimmune Activation
Boenisch, O., D’Addio, F., Watanabe, T., Elyaman, W., Magee, C. N., Yeung, M. Y., Padera, R. F., Rodig, S. J., Murayama, T., Tanaka, K., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903435 · Cited by 76
Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis
Fairweather, D., Petri, M., Coronado, M. J., & Cooperr, L. T. (2012) · Expert Review of Clinical Immunology · doi:10.1586/eci.12.10 · Cited by 75
Self-citationType B Coxsackieviruses and Their Interactions with the Innate and Adaptive Immune Systems
Kemball, C. C., Alirezaei, M., & Whitton, J. L. (2010) · Future Microbiology · doi:10.2217/fmb.10.101 · Cited by 79
“myocarditis [16].”
TIM-1 and TIM-3 proteins in immune regulation
Su, E. W., Lin, J., & Kane, L. (2008) · Cytokine · doi:10.1016/j.cyto.2008.06.013 · Cited by 73
“The authors compared the levels of Tim-3 on infected male and female BALB/c mice and found that there was significantly less Tim-3 on mast cells, macrophages and CD4 T cells isolated from the hearts of CVB3-infected male mice [53].”
BackgroundBruno, K. A., Mathews, J. E., Yang, A. L., Frisancho, J. A., Scott, A. J., Greyner, H. D., Molina, F. A., Greenaway, M. S., Cooper, G. M., Bucek, A., et al. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00598 · Cited by 73
“, TLR4, caspase-1, IL-1β, and IL-18) are upregulated in the heart during viral myocarditis in male mice and that testosterone elevates this pathway on mast cells and macrophages during the innate and adaptive immune response to CVB3 infection in our model (44, 46).”
BackgroundMethodInfluentialSelf-citationMyocarditis associated with COVID-19 vaccination
Buoninfante, A., Andeweg, A. C., Genov, G., & Cavaleri, M. (2024) · npj Vaccines · doi:10.1038/s41541-024-00893-1 · Cited by 81
Abston, E. D., Barin, J. G., Cihakova, D., Bucek, A., Coronado, M. J., Brandt, J. E., Bedja, D., Kim, J. B., Georgakopoulos, D., Gabrielson, K. L., et al. (2012) · Circulation: Heart Failure · doi:10.1161/circheartfailure.111.963769 · Cited by 69
“rIL-33 increases cardiac IL-33, IL-4, IL-1 IL-6 and serum sST2, and alters remodeling during acute CVB3 myocarditis IL-33 has been demonstrated to promote Th2 responses.(12,25,29) For this reason we examined the effect of rIL-33 or rST2 treatment on Th2-associated cytokines in the heart (e.”
Self-citationWang, S., Cao, C., Piao, H., Li, Y., Yu, T., Zhang, X., Zhang, D., Sun, C., Zhu, R., Wang, Y., et al. (2015) · Scientific Reports · doi:10.1038/srep09013 · Cited by 65
Autoimmune Myocarditis, Valvulitis, and Cardiomyopathy
Myers, J. M., Fairweather, D., Huber, S. A., & Cunningham, M. W. (2013) · Current Protocols in Immunology · doi:10.1002/0471142735.im1514s101 · Cited by 63
“Male BALB/c mice develop more severe acute and chronic myocarditis/DCM than females (Frisancho-Kiss et al., 2007, 2009; Onyimba et al., 2011; Coronado et al., 2012).”
BackgroundSelf-citationTim-3: Expression on immune cells and roles at the maternal-fetal interface
Hu, X., Tang, M., Mor, G., & Liao, A. (2016) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2016.10.113 · Cited by 58
Sex-specific environmental influences on the development of autoimmune diseases
Tiniakou, E., Costenbader, K. H., & Kriegel, M. A. (2013) · Clinical Immunology · doi:10.1016/j.clim.2013.02.011 · Cited by 61
“Interestingly, antiphospholipid antibodies can be induced by estrogen in mice [74, 78], but a link between sex, microbial agents and antiphospholipid syndrome has not yet been established.”
BackgroundOnyimba, J. A., Coronado, M. J., Garton, A. E., Kim, J. B., Bucek, A., Bedja, D., Gabrielson, K. L., Guilarte, T. R., & Fairweather, D. (2011) · Biology of Sex Differences · doi:10.1186/2042-6410-2-2 · Cited by 57
“More severe disease in males is associated with increased Toll-like receptor (TLR)4 expression on mast cells and macrophages in the heart during acute myocarditis and in the spleen at 12 h pi [12-14].”
BackgroundInfluentialSelf-citationCardiomyopathies: Classification, Diagnosis, and Treatment
Maisch, B., Noutsias, M., Ruppert, V., Richter, A., & Pankuweit, S. (2011) · Heart Failure Clinics · doi:10.1016/j.hfc.2011.08.014 · Cited by 56
Roberts, B. J., Dragon, J. A., Moussawi, M., & Huber, S. A. (2012) · Biology of Sex Differences · doi:10.1186/2042-6410-3-25 · Cited by 54
“While microarray analysis showed sex differences in TLR2 expression, a role for TLR4 in CVB3 myocarditis has also been shown [25-27].”
BackgroundResultMaisch, B., & Pankuweit, S. (2012) · Heart Failure Reviews · doi:10.1007/s10741-012-9362-7 · Cited by 53
Roberts, B. J., Moussawi, M., & Huber, S. A. (2012) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2012.06.005 · Cited by 54
Sex-related Differences in Mast Cell Activity and Doxorubicin Toxicity
Zhang, J., Knapton, A. D., Lipshultz, S. E., Cochran, T. R., Hiraragi, H., & Herman, E. H. (2013) · Toxicologic Pathology · doi:10.1177/0192623313482778 · Cited by 53
“Mast cells (MCs) and macrophages contain estrogen and androgen receptors (Frisancho-Kiss et al. 2007).”
BackgroundDistinct Th17 inductions contribute to the gender bias in CVB3-induced myocarditis
Li, Z., Yue, Y., & Xiong, S. (2013) · Cardiovascular Pathology · doi:10.1016/j.carpath.2013.02.004 · Cited by 52
Clinical Characteristics and Mechanisms of Acute Myocarditis
Heymans, S. R. B., Linthout, S. V., Kraus, S., Cooper, L. T., & Ntusi, N. (2024) · Circulation Research · doi:10.1161/circresaha.124.324674 · Cited by 52
“52 Beyond the impact of biological sex on the immune response and viral myocarditis, the genetic background is of relevance in myocarditis, as outlined below.”
BackgroundAutoimmunity in viral myocarditis
Reddy, J., Massilamany, C., Buskiewicz, I., & Huber, S. A. (2013) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e3283620036 · Cited by 50
The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue
Lucas, K., Morris, G., Anderson, G., & Maes, M. H. J. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527314666150317224645 · Cited by 50
Bruestle, K., Hackner, K., Kreye, G., & Heidecker, B. (2020) · Current Cardiology Reports · doi:10.1007/s11886-020-01278-1 · Cited by 53
Testosterone, cardiomyopathies, and heart failure
Diaconu, R., Donoiu, I., Mirea, O., & Bălşeanu, T. A. (2021) · Asian Journal of Andrology · doi:10.4103/aja.aja_80_20 · Cited by 51
Abston, E. D., Coronado, M. J., Bucek, A., Onyimba, J. A., Brandt, J. E., Frisancho, J. A., Kim, E., Bedja, D., Sung, Y.-K., Radtke, A. J., et al. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00516.2011 · Cited by 48
Self-citationSex-Specific Differences of the Inflammatory State in Experimental Autoimmune Myocarditis
Barcena, M. L., Jeuthe, S., Niehues, M. H., Pozdniakova, S., Haritonow, N., Kühl, A. A., Messroghli, D. R., & Regitz-Zagrosek, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.686384 · Cited by 47
Intricacies of cardiac damage in coxsackievirus B3 infection: Implications for therapy
Massilamany, C., Gangaplara, A., & Reddy, J. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.09.136 · Cited by 45
“Furthermore, expression of TLRs can occur gender dependently: elevated expression of TLR-4 in the macrophages of male mice contributed to mortalities in CVB3infected animals, but the underlying mechanisms are unknown [70, 71].”
BackgroundNyland, J. F., Fairweather, D., Shirley, D. L., Davis, S., Rose, N. R., & Silbergeld, E. K. (2011) · Toxicological Sciences · doi:10.1093/toxsci/kfr264 · Cited by 47
“Male BALB/cJ (BALB/c) mice (6–8 weeks old; The Jackson Laboratory) were used in this study because myocarditis and DCM are more prevalent in men (Roger et al., 2011) and male BALB/c mice develop more severe myocarditis and DCM (Frisancho-Kiss et al., 2006, 2007).”
BackgroundMethodSelf-citationSex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy
Jain, A., Norton, N., Bruno, K. A., Cooper, L. T., Atwal, P. S., & Fairweather, D. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10112289 · Cited by 48
Self-citationLiu, L., Yue, Y., & Xiong, S. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.07.021 · Cited by 46
“Actually, similar results have also been reported by other groups [6,61].”
BackgroundResultZhang, Z. (2010) · Oncology Reports · doi:10.3892/or_00000909 · Cited by 46
Riad, A., Westermann, D., Escher, F., Becher, P. M., Savvatis, K., Lettau, O., Heimesaat, M. M., Bereswill, S., Volk, H., Schultheiß, H., et al. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01188.2009 · Cited by 44
(2022) · doi:10.1016/j.isci.2022.103865 · Cited by 43
“On the other hand, the Th2 cells could attenuate acute myocarditis (Frisancho-Kiss et al., 2007; Liu and Huber, 2011) but can also promote cardiac remodeling events, leading to chronic myocarditis/DCM associated with cardiac fibrosis (Abston et al.”
BackgroundQi, X., Xu, J., Wang, F., & Xiao, J. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/162934 · Cited by 46
“Therefore, increased cholesterol metabolism associated with TSPO during the immune response to CVB3 infection may drive the proinflammatory reaction of myocarditis [81, 82].”
BackgroundThe sex and gender dimensions of COVID-19: A narrative review of the potential underlying factors
Mourosi, J. T., Anwar, S., & Hosen, M. J. (2022) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2022.105338 · Cited by 51
Innate and adaptive immune responses against picornaviruses and their counteractions: An overview
Dotzauer, A. (2012) · World Journal of Virology · doi:10.5501/wjv.v1.i3.91 · Cited by 40
Fairweather, D., Coronado, M. J., Garton, A. E., Dziedzic, J. L., Bucek, A., Cooper, L. T., Brandt, J. E., Alikhan, F. S., Wang, H., Endres, C. J., et al. (2014) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-013-9538-0 · Cited by 39
“Previously, we showed in a mouse model of CVB3myocarditis that testosterone increases CD11b expression on cardiac macrophages during acute myocarditis in male mice [24, 25].”
BackgroundMethodInfluentialSelf-citationSex Hormone Receptor Expression in the Immune System
Buskiewicz, I. A., Huber, S. A., & Fairweather, D. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802388-4.00004-5 · Cited by 38
Self-citationSteffens, S., Linthout, S. V., Sluijter, J. P. G., Tocchetti, C. G., Thum, T., & Madonna, R. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa137 · Cited by 38
Coagulation, Protease-Activated Receptors, and Viral Myocarditis
Antoniak, S., & Mackman, N. (2013) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-013-9515-7 · Cited by 37
Influence of Cinnamaldehyde on Viral Myocarditis in Mice
Ding, Y., Wang, S., Qiu, L., Gangtao, Z., & Jing-feng, X. (2010) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e3181dd3b43 · Cited by 36
Sexual dimorphisms of mRNA and miRNA in human/murine heart disease
Tsuji, M., Kawasaki, T., Matsuda, T., Arai, T., Gojo, S., & Takeuchi, J. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177988 · Cited by 36
Clinical Presentation and Laboratory Findings in Men Versus Women with Myocarditis
Patriki, D., Kottwitz, J., Berg, J., Landmesser, U., Lüscher, T. F., & Heidecker, B. (2019) · Journal of Women s Health · doi:10.1089/jwh.2018.7618 · Cited by 36
Metadata
- Authors
- Frisancho-Kiss, S., Davis, S. E., Nyland, J. F., Frisancho, J. A., Cihakova, D., Barrett, M. A., Rose, N. R., & Fairweather, D.
- Affiliations
- Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health and School of Medicine , Baltimore, MD 21205
- Johns Hopkins University (US)
- Department of Pathology, Johns Hopkins University, Bloomberg School of Public Health and School of Medicine , Baltimore, MD 21205
- Corresponding author
- Fairweather, DeLisa
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06-01
- Volume
- 178
- Issue
- 11
- Pages
- 6710-6714
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1500123828
- Cited by
- 212
- References
- 24
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 11 · 2023: 17 · 2022: 13 · 2021: 9 · 2020: 9 · 2019: 10 · 2018: 6 · 2017: 7 · 2016: 7 · 2015: 11 · 2014: 19 · 2013: 13 · 2012: 23
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL087033, HL077611, HL 70729, R01HL070729, HL087033)
- National Institute of Environmental Health Sciences (ES03819, P30ES003819, T32ES007141)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- sex differences, inflammatory heart disease, TLR4, TIM-3, coxsackievirus B3, myocarditis, regulatory T cells, interferon-gamma, IL-4, innate and adaptive immunity, viral infection, cardiac inflammation
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Coxsackievirus Infections, Female, Macrophages, Male, Mast Cells, Mice, Inbred BALB C, Mice, Transgenic, Myocarditis, Receptors, Virus, Sex Characteristics, Signal Transduction, Up-Regulation, Mice, Knockout, Receptor Cross-Talk, Enterovirus B, Human, Toll-Like Receptor 4, Mice
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