TY - JOUR
T1 - 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
AU - Frisancho-Kiss, Sylvia
AU - Coronado, Michael J.
AU - Frisancho, J. Augusto
AU - Lau, Vivian M.
AU - Rose, Noel R.
AU - Klein, Sabra L.
AU - Fairweather, De Lisa
N1 - Funding Information:
We thank P.G. Fallon for technical assistance. This research was supported by National Institutes of Health Grants R01 HL087033 (D.F.), R01 HL67290 (N.R.R.), R01 AI054995 (S.L.K.) and P30 ES03819.
PY - 2009/7
Y1 - 2009/7
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Cytokines
KW - Macrophages
KW - Myocarditis
KW - Sex differences
KW - Th2
KW - Tim-3
KW - Tolerance
KW - Treg
KW - Virus
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U2 - 10.1016/j.bbi.2008.12.002
DO - 10.1016/j.bbi.2008.12.002
M3 - Article
C2 - 19126426
AN - SCOPUS:68649115262
SN - 0889-1591
VL - 23
SP - 649
EP - 657
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
IS - 5
ER -