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Cited by 91Viral Infections and Immunology ResearchCardiac Fibrosis and Remodelinginterferon and immune responses

Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rβ1 signaling and IFN-γ increase inflammation in males independent from STAT4

Frisancho-Kiss, Sylvia, Nyland, Jennifer F., Davis, Sarah E., Augusto Frisancho, J., Barrett, Masheka A., Rose, Noel R., Fairweather, DeLisa·2006·Brain Research
DOI 10.1016/j.brainres.2006.08.003
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Abstract

Cardiovascular disease is the number one killer of men and women in North America. Male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe inflammatory heart disease compared to female mice, similar to the increased heart disease that occurs in men. We show here that increased inflammation in male mice is not due to increased viral replication in the heart, but associated with increased proinflammatory cytokines IL-1beta, IL-18 and IFN-gamma. We have previously reported that IL-12Rbeta1 signaling increases CVB3-induced myocarditis and IL-1beta/IL-18 levels in males, while IL-12(p35)/STAT4-induced IFN-gamma does not alter the severity of acute disease. However, whether differences exist between males and females in these two cytokine signaling pathways is unknown. In this study, we examined sex differences in 1) IL-12Rbeta1 signaling or 2) STAT4/IFN-gamma pathways following CVB3 infection in BALB/c mice. We found that male and female mice deficient in IL-12Rbeta1 had decreased inflammation and viral replication in the heart, indicating that IL-12Rbeta1 signaling increases myocarditis in both sexes. In contrast, STAT4 deficiency did not alter the sex difference in myocarditis, with males maintaining increased inflammation over females. IFN-gamma deficient males, however, had decreased myocarditis and viral replication compared to females. Thus, IFN-gamma increases inflammation in males independent from STAT4. These results demonstrate that sex differences gr…

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Crossref · 10.1016/j.brainres.2006.08.003

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  • Tim-3 is a receptor 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.

    “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 [146]

  • 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 this response leads to rapid increases in TNF, IL-1β, IL-6, and IFNγ in many organs including the heart.

    “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 [146]

  • The TLR4, caspase-1, and NLRP3 pathways are upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3-only models and increase IL-1β and IL-18 levels in the heart.

    “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 [146]

  • Elevated TLR4 and IL-1β 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.

    “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 [146]

  • The majority of immune cells in the heart during acute myocarditis in EAM, autoimmune CVB3 myocarditis model, and humans are CD11b+ cells that include neutrophils, macrophages, mast cells, and some dendritic cells.

    “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 [146]

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Authors
Frisancho-Kiss, S., Nyland, J. F., Davis, S. E., Augusto Frisancho, J., Barrett, M. A., Rose, N. R., & Fairweather, D.
Affiliations
Johns Hopkins University (US)
Corresponding author
Fairweather, DeLisa
ORCID
Venue
Brain Research
Publisher
Elsevier BV
Published
2006-12
Volume
1126
Issue
1
Pages
139-147
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/j.brainres.2006.08.003
OpenAlex
W2094827930
Cited by
90
References
54
Citations by year
2026: 5 · 2025: 3 · 2024: 8 · 2023: 9 · 2022: 6 · 2021: 4 · 2020: 4 · 2018: 1 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 6 · 2013: 1 · 2012: 8
FWCI
3.28
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL 67290, R01HL067290, HL 70729, R01HL070729)
  • National Institute of Allergy and Infectious Diseases (AI 51835, R21AI051835)
  • National Institute of Environmental Health Sciences (ES03819, P30ES003819, R00ES015426, T32ES007141)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
coxsackievirus B3, myocarditis, sex differences, interferon-gamma, STAT4, IL-1β, IL-18, inflammatory cytokines, viral replication, cardiac inflammation, viral cardiomyopathy
MeSH terms
Animals, Coxsackievirus Infections, Disease Models, Animal, Enterovirus, Female, Interferon-gamma, Male, Mice, Inbred BALB C, Myocarditis, Myocardium, Sex Characteristics, Virus Replication, Signal Transduction, Mice, Knockout, Disease Progression, STAT4 Transcription Factor, Mice, Receptors, Interleukin-12

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