Abstract
Background
Viral myocarditis is a widespread cardiac disease associated with inflammation and
myocardial injury and is predominantly caused by coxsackievirus B3 (CVB3) infection
in humans as well as in mice. CVB3-induced myocarditis shows sexually dimorphic sensitivity
and is more prevalent in male mice. Our previous studies showed that natural killer
(NK) cells played an indispensable role in CVB3-induced myocarditis, and female mice
exhibited less pathological cardiac interferon gamma (IFN-γ)+ NK cell infiltration than did male mice. However, the precise mechanisms were not
well elucidated.
Methods
We investigated the influence of estrogen on cardiac IFN-γ+ NK cell enrichment in CVB3-induced myocarditis and explored the underlying molecular
mechanism.
Results
In this study, we found that CVB3 stimulation could clearly induce IFN-γ expression
by NK cells; however, this trend could be blunted by estrogen treatment. Consistently,
ovariectomized female mice with decreased estrogen levels exhibited substantially
increased enrichment of cardiac IFN-γ+ NK cells and displayed significantly aggravated myocarditis. Similarly, estrogen-treated
male mice showed less cardiac IFN-γ+ NK cell infiltration, accompanied by significantly alleviated viral myocarditis.
In sharp contrast, sexually immature female and male mice (with similar estrogen levels)
showed comparable levels of cardiac IFN-γ+ NK cell infiltration and similar levels of myocarditis severity. Upon further exploration
of the underlying mechanisms, we found that estrogen could downregulate expression
of Th1-specific T box transcription factor (T-bet), the key transcription factor associated
with IFN-γ production, in CVB3-stimulated NK cells.
Conclusions
Overall, this study might help us understand the mechanism of increased cardiac infiltration
by IFN-γ+ NK cells in CVB3-infected male mice compared with that in female mice and might provide
new clues for the sex bias in CVB3-induced myocarditis.
Résumé
Introduction
La myocardite d’origine virale est une cardiopathie répandue associée à une inflammation
et à des lésions myocardiques et est principalement causée par l’infection à virus
Coxsackie B3 (CVB3) chez les humains ainsi que chez les souris. La myocardite induite
par le CVB3 montre une sensibilité sexuellement dimorphique et est plus répandue chez
les souris mâles. Les études que nous avons réalisées précédemment ont montré que
les cellules tueuses naturelles (NK, de l’anglais natural killer) jouaient un rôle indispensable dans la myocardite induite par le CVB3, et que les
souris femelles montraient moins d’infiltration cardiaque pathologique de cellules
NK par l’interféron gamma (IFN-γ)+. Toutefois, les mécanismes précis restent mal élucidés.
Méthodes
Nous avons examiné l’influence des œstrogènes sur l’enrichissement cardiaque des cellules
NK en IFN-γ+ dans la myocardite induite par le CVB3 et étudié le mécanisme moléculaire sous-jacent.
Résultats
Dans cette étude, nous avons observé que la stimulation du CVB3 pourrait de toute
évidence induire l’expression de l’IFN-γ par les cellules NK. Toutefois, le traitement
œstrogénique pourrait atténuer cette tendance. Invariablement, les souris femelles
ovariectomisées dont les concentrations en œstrogènes étaient moindres ont montré
une augmentation substantielle de l’enrichissement cardiaque des cellules NK en IFN-γ
et ont subi des myocardites significativement plus compliquées. De la même façon,
les souris mâles ayant reçu un traitement œstrogénique ont montré moins d’infiltration
cardiaque de cellules NK par l’IFN-γ, et des myocardites d’origine virale significativement
moins compliquées. Tout à fait à l’opposé, les souris femelles et mâles immatures
sexuellement (dont les concentrations en œstrogènes sont similaires) ont montré des
concentrations comparables d’infiltration cardiaque de cellules NK par l’IFN-γ et
des degrés similaires de gravité des myocardites. Après une exploration plus poussée
des mécanismes sous-jacents, nous avons observé que les œstrogènes pourraient réguler
à la baisse l’expression des facteurs de transcription T-bet (T-box expressed in T
cells) spécifiques aux cellules Th1, le principal facteur de transcription associé
à la production de l’IFN-γ dans les cellules NK stimulées par le CVB3.
Conclusions
Dans l’ensemble, cette étude favoriserait notre compréhension des mécanismes d’augmentation
de l’infiltration cardiaque de cellules NK par l’IFN-γ+ chez les souris mâles infectées par le CVB3 par rapport aux souris femelles et offrirait
de nouveaux indices sur les biais sexuels de la myocardite induite par le CVB3.
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References
- The group B coxsackieviruses and myocarditis.Rev Med Virol. 2001; 11: 355-368
- Update on coxsackievirus B3 myocarditis.Curr Opin Rheumatol. 2012; 24: 401-407
- Myocarditis: a clinical overview.Curr Cardiol Rep. 2017; 19: 63
- Differential macrophage polarization in male and female BALB/c mice infected with coxsackievirus B3 defines susceptibility to viral myocarditis.Circ Res. 2009; 105: 353-364
- Distinct Th17 inductions contribute to the gender bias in CVB3-induced myocarditis.Cardiovasc Pathol. 2013; 22: 373-382
- The role of sex differences in autophagy in the heart during coxsackievirus B3-induced myocarditis.J Cardiovasc Transl Res. 2014; 7: 182-191
- Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis.Biol Sex Differ. 2011; 2: 8
- Sex hormones and the genesis of autoimmunity.Arch Dermatol. 2006; 142: 371-376
- Sex differences in the myocardial inflammatory response to acute injury.Shock. 2005; 23: 1-10
- Sex hormones and the immune response in humans.Hum Reprod Update. 2005; 11: 411-423
- Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone.FEMS Immunol Med Microbiol. 2003; 38: 13-22
- Estrogen regulates the IFN-gamma promoter.J Immunol. 1991; 146: 4362-4367
- Effect of estrogens on the interferon-gamma producing cell population of mouse splenocytes.Biosci Biotechnol Biochem. 2006; 70: 47-53
- Effects of long-term estrogen treatment on IFN-gamma, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice.Cytokine. 2001; 14: 208-217
- ERbeta and ERalpha differentially regulate NKT and Vgamma4(+) T-cell activation and T-regulatory cell response in coxsackievirus B3 infected mice.J Clin Cell Immunol. 2015; 6: 1-9
- Monocytic myeloid-derived suppressor cells from females, but not males, alleviate CVB3-induced myocarditis by increasing regulatory and CD4(+)IL-10(+) T cells.Sci Rep. 2016; 6: 22658
- Sex and gender differences in myocarditis and dilated cardiomyopathy.Curr Probl Cardiol. 2013; 38: 7-46
- NK cells in mucosal defense against infection.Biomed Res Int. 2014; 2014: 413982
- Natural killer cells in viral infection: more than just killers.Immunol Rev. 2006; 214: 239-250
- Structural insights into activation of antiviral NK cell responses.Immunol Rev. 2012; 250: 239-257
- NK-derived IFN-gamma/IL-4 triggers the sexually disparate polarization of macrophages in CVB3-induced myocarditis.J Mol Cell Cardiol. 2014; 76: 15-25
- The influence of sex and gender on the immune response.Autoimmun Rev. 2012; 11: A479-A485
- Sex drives dimorphic immune responses to viral infections.J Immunol. 2017; 198: 1782-1790
- Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway.J Virol. 2002; 76: 3365-3373
- A novel transcription factor, T-bet, directs Th1 lineage commitment.Cell. 2000; 100: 655-669
- Molecular biology and pathogenesis of viral myocarditis.Annu Rev Pathol. 2008; 3: 127-155
- Myocarditis in auto-immune or auto-inflammatory diseases.Autoimmun Rev. 2017; 16: 811-816
- Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity.Methods. 2007; 41: 118-122
- Generation of cytotoxic T lymphocytes during coxsackievirus B-3 infection. III. Role of sex.J Immunol. 1977; 119: 591-597
- Hormonal regulation of CD4(+) T-cell responses in coxsackievirus B3-induced myocarditis in mice.J Virol. 1999; 73: 4689-4695
- Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333
- Protective effects of estrogen on the cardiovascular system.Am J Cardiol. 2002; 89 ([discussion: 17E-18E]): 12E-17E
- Innate and adaptive immunity in female genital tract: cellular responses and interactions.Immunol Rev. 2005; 206: 306-335
- Hormone-replacement therapy: current thinking.Nat Rev Endocrinol. 2017; 13: 220-231
- Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.JAMA. 1998; 280: 605-613
- Estrogen plus progestin and the risk of coronary heart disease.N Engl J Med. 2003; 349: 523-534
- The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective.Climacteric. 2012; 15: 217-228
- Best practice for HRT: unpicking the evidence.Br J Gen Pract. 2016; 66: 597-598
- Estrogen receptors regulate innate immune cells and signaling pathways.Cell Immunol. 2015; 294: 63-69
- Estrogen receptor alpha inhibits IL-1beta induction of gene expression in the mouse liver.Endocrinology. 2002; 143: 2559-2570
- Sex affects immunity.J Autoimmun. 2012; 38: J282-J291
- Estrogen and antiestrogen modulation of the levels of mouse natural killer activity and large granular lymphocytes.Cell Immunol. 1987; 106: 191-202
- The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells.Gynecol Oncol. 2001; 81: 254-262
- Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors.Int Immunopharmacol. 2007; 7: 1765-1775
- Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis.Blood. 1998; 92: 1044-1054
- Estrogen induction of the granzyme B inhibitor, proteinase inhibitor 9, protects cells against apoptosis mediated by cytotoxic T lymphocytes and natural killer cells.Endocrinology. 2006; 147: 1419-1426
- IFN-gamma production dominates the early human natural killer cell response to Coxsackievirus infection.Cell Microbiol. 2008; 10: 426-436
- 17beta-estradiol downregulates interferon regulatory factor-1 in murine splenocytes.J Mol Endocrinol. 2006; 37: 421-432
- Estrogenic compounds suppressed interferon-gamma production in mouse splenocytes through direct cell-cell interaction.In Vitro Cell Dev Biol Anim. 2003; 39: 383-387
- Mediation of the immunomodulatory effect of beta-estradiol on inflammatory responses by inhibition of recruitment and activation of inflammatory cells and their gene expression of TNF-alpha and IFN-gamma.Int Arch Allergy Immunol. 2000; 121: 235-245
- Role of sex steroid hormones in bacterial-host interactions.Biomed Res Int. 2013; 2013: 928290
- T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells.Immunity. 2004; 20: 477-494
- Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells.Science. 2002; 295: 338-342
- T-bet as a key regulator of mucosal immunity.Immunology. 2016; 147: 367-376
- T-bet in disease.Nat Immunol. 2011; 12: 597-606
- IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12.Mol Immunol. 2007; 44: 1808-1814
- Medium-dose estrogen ameliorates experimental autoimmune encephalomyelitis in ovariectomized mice.J Immunotoxicol. 2016; 13: 885-896
Article info
Publication history
Published online: January 05, 2018
Accepted:
January 3,
2018
Received:
October 6,
2017
Footnotes
See page 500 for disclosure information.
See editorial by Howlett, pages 354–355 of this issue.
Identification
Copyright
© 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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Access this article on ScienceDirectLinked Article
- Coxsackievirus B3-Induced Myocarditis: New Insights Into a Female AdvantageCanadian Journal of CardiologyVol. 34Issue 4
- PreviewMyocarditis is an inflammatory cardiomyopathy that is characterized by the inflammation of cardiac muscle cells.1 Although the disease itself can be life-threatening, its prognosis as well as pathogenesis vary widely. Myocarditis can be acute, subacute, or chronic and can feature either focal or widespread myocardial damage.2 Unsurprisingly, this leads to a variable degree of myocardial injury that can range from a fully recoverable syndrome to systolic dysfunction and dilated cardiomyopathy that results in death or requires heart transplantation.
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