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

Sylvia Frisancho-Kiss, Michael J. Coronado, J. Augusto Frisancho, Vivian M. Lau, Noel R. Rose, Sabra L. Klein, DeLisa Fairweather

Research output: Contribution to journalArticle

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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-1β and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1-IL-4Rlo 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.

Original languageEnglish (US)
Pages (from-to)649-657
Number of pages9
JournalBrain, Behavior, and Immunity
Volume23
Issue number5
DOIs
StatePublished - Jul 2009
Externally publishedYes

Fingerprint

Th2 Cells
Enterovirus
Myocarditis
Macrophages
T-Lymphocytes
Inflammation
Interleukins
Gonadal Steroid Hormones
Regulatory T-Lymphocytes
Interleukin-10
Coxsackievirus Infections
Interleukin-1
Interleukin-4
Population
Testosterone
Testis
Heart Diseases
Anti-Inflammatory Agents
Cardiovascular Diseases
Incidence

Keywords

  • Autoimmunity
  • Cytokines
  • Macrophages
  • Myocarditis
  • Sex differences
  • Th2
  • Tim-3
  • Tolerance
  • Treg
  • Virus

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems

Cite this

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. / Frisancho-Kiss, Sylvia; Coronado, Michael J.; Frisancho, J. Augusto; Lau, Vivian M.; Rose, Noel R.; Klein, Sabra L.; Fairweather, DeLisa.

In: Brain, Behavior, and Immunity, Vol. 23, No. 5, 07.2009, p. 649-657.

Research output: Contribution to journalArticle

Frisancho-Kiss, Sylvia ; Coronado, Michael J. ; Frisancho, J. Augusto ; Lau, Vivian M. ; Rose, Noel R. ; Klein, Sabra L. ; Fairweather, DeLisa. / 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. In: Brain, Behavior, and Immunity. 2009 ; Vol. 23, No. 5. pp. 649-657.
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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-1β and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1-IL-4Rlo 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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AU - Coronado, Michael J.

AU - Frisancho, J. Augusto

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AU - Rose, Noel R.

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