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Canadian Journal of Cardiology

Sex Hormone Contributes to Sexually Dimorphic Susceptibility in CVB3-Induced Viral Myocarditis via Modulating IFN-γ+ NK Cell Production

  • Nannan Zhou
    Affiliations
    Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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  • Yan Yue
    Correspondence
    Dr Yan Yue, Institutes of Biology and Medical Science, Soochow University, 199 Ren-Ai Rd, Suzhou, Jiangsu 215123, P.R. China. Tel.: +1-86-512-65881255; fax: +1-86-512-65881255.
    Affiliations
    Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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  • Sidong Xiong
    Correspondence
    Corresponding authors: Dr Sidong Xiong, Institutes of Biology and Medical Science, Soochow University, 199 Ren-Ai Rd, Suzhou, Jiangsu 215123, P.R. China. Tel.: +1-86-512-65881255; fax: +1-86-512-65881255.
    Affiliations
    Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, People's Republic of China
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Published:January 05, 2018DOI:https://doi.org/10.1016/j.cjca.2018.01.002

      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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      Linked Article

      • Coxsackievirus B3-Induced Myocarditis: New Insights Into a Female Advantage
        Canadian Journal of CardiologyVol. 34Issue 4
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          Myocarditis 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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