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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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
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In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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“The accuracy of cMRI depends on the amount of scar tissue present”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [124]
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BackgroundSelf-citation
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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