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Cited by 143Viral Infections and Immunology ResearchCardiac Fibrosis and RemodelingAtherosclerosis and Cardiovascular Diseases

Gonadectomy of male BALB/c mice increases Tim-3+ alternatively activated M2 macrophages, Tim-3+ T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis

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Frisancho-Kiss, Sylvia, Coronado, Michael J., Frisancho, J. Augusto, Lau, Vivian M., Rose, Noel R., Klein, Sabra L., Fairweather, DeLisa·2009·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2008.12.002PMC PMC3148833
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Abstract

The incidence of cardiovascular disease, including inflammatory heart diseases like myocarditis, is increased in men. Similarly, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe acute inflammation in the heart compared to females. To better understand the effect of male sex hormones on cardiac inflammation, we gonadectomized (Gdx) male BALB/c mice and examined acute CVB3-induced myocarditis compared to sham controls. Viral replication in the heart was not significantly altered between Gdx and sham mice. However, gonadectomy significantly reduced testosterone levels and inflammation in the heart. FACS analysis of cell populations isolated from the heart revealed that CD11b(+) cells were significantly reduced in Gdx males. However, a GR1(+)F4/80(+) subset of CD11b(+) cells was significantly increased. Because this subset also expressed the interleukin (IL)-4R and IL-10, we refer to these cells as "alternatively activated" or M2 macrophages. A greater percentage of M2 macrophages in Gdx males expressed the inhibitory receptor Tim-3, while fewer expressed IL-1beta and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1(-)IL-4R(lo) macrophages did not. Additionally, IL-4(+)CD4(+) Th2 cells, Foxp3(+) regulatory T (Treg) cells and Tim-3(+)CD4(+) T cells were significantly increased in the heart following Gdx. Thus, we report for the first time that the inhibitory receptor Tim-3 is expressed on M2 macrophages. Our findings show that sex hormones and/or other mediators released from the testes inhibit anti-inflammatory populations in the heart including Tim-3(+) M2, Tim-3(+)CD4(+) T cells, Th2 and Treg resulting in more severe acute cardiac inflammation in males following CVB3 infection.

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Crossref · 10.1016/j.bbi.2008.12.002

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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 [125]

    The Introduction (page unavailable) says Tim-3 is upregulated on mast cells and macrophages after CVB3 infection and describes it as an inhibitory receptor; the Discussion (page unavailable) identifies M2 macrophages as a source of IL-10. But Results §3.9 reports that gonadectomy increased Tim-3-positive M2 macrophages while decreasing IL-10-positive M2 macrophages. The paper does not show increased IL-10 release associated with Tim-3, and its evidence for inhibition of T-cell responses is indirect. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Men have more neutrophils and monocytes, whereas women have more T cells, similar to autoimmune myocarditis.

    “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 [125]

    Results §3.4 reports more CD11b+ cells in male mouse hearts and more Tim-3+CD4+ T cells and regulatory T cells in female mouse hearts during acute CVB3-induced myocarditis. The paper does not establish that men specifically have more neutrophils: §3.4 says neutrophils were not examined in this study. The claim also generalizes these mouse findings to men and women. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Tim-3 is an important regulator of T cells following TLR4 activation and displays sex differences during CVB3 myocarditis.

    “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 [125]

    The Introduction and Discussion (pages not provided) describe sex differences in Tim-3 expression during CVB3 myocarditis and link Tim-3 to T-cell populations. The Discussion suggests cross-regulation of TLR4 and Tim-3 signaling on M2 macrophages, but does not establish that Tim-3 regulates T cells following TLR4 activation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 5

  1. Dec GW Cooper LT Jr. Introduction to clinical myocarditis Myocarditis: From Bench to Bedside 2003 157 281 Humana Press Totowa, New Jersey
  2. Fairweather D Rose NR Luebke R House R Kimber I Immunopathogenesis of autoimmune disease Immunotoxicology and Immunopharmacology 2007a 423 436 CRC Press Boca Raton 3rd Ed.
  3. Fairweather D Frisancho-Kiss S Yusung SA Barrett MA Gatewood SJL Davis SE Njoku DB Rose NR IFN-γ protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines TGF-β1, IL-1β, and IL-4 in the heart Am. J. Pathol 2004a 165 1883 1894 15579433 PMC1618717
  4. Melchert RB Kennedy RH Acosta D Jr. Acosta D Jr. Cardiovascular effects of steroidal agents Cardiovascular Toxicology 2001 425 475 Taylor & Francis London
  5. Rosamond W Flegal K Furie K Go A Greenlund K Haase N Hailpern SM Ho M Howard V Kissela B Kittner S Lloyd-Jones D McDermott M Meigs J Moy C Nichol G O'Donnell C Roger V Sorlie P Steinberger J Thom T Wilson M Hong Y American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics- 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2008 117 e25 e146 18086926

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Authors
Frisancho-Kiss, S., Coronado, M. J., Frisancho, J. A., Lau, V. M., Rose, N. R., Klein, S. L., & Fairweather, D.
Affiliations
Johns Hopkins University (US)
Corresponding author
Fairweather, DeLisa
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2009-07
Volume
23
Issue
5
Pages
649-657
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2008.12.002
PMC
PMC3148833
OpenAlex
W2028001783
Cited by
143
References
66
Citations by year
2026: 6 · 2025: 5 · 2024: 7 · 2023: 12 · 2022: 14 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 7 · 2014: 12 · 2013: 9 · 2012: 13
FWCI
3.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL087033, R01HL067290)
  • National Institute of Allergy and Infectious Diseases (R01AI054995)
  • National Institute of Environmental Health Sciences (P30ES003819)
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 › Atherosclerosis and Cardiovascular Diseases
Keywords
gonadectomy, TIM-3, M2 macrophages, coxsackievirus B3, viral myocarditis, sex hormones, testosterone, Th2 cells, regulatory T cells, TLR4, IL-10, IL-4, CD11b+ cells
MeSH terms
Hepatitis A Virus Cellular Receptor 2, Acute Disease, Animals, Coxsackievirus Infections, Macrophage Activation, Male, Mice, Inbred BALB C, Myocarditis, Myocardium, Orchiectomy, Receptors, Virus, Testosterone, Virus Replication, Cytokines, Leukocyte Common Antigens, Th2 Cells, Enterovirus B, Human, CD11b Antigen, T-Lymphocytes, Regulatory, Mice

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