Sexual Differentiation of Th17Cells in CVB3-induced Myocarditis and Its Underlying Mechanisms
|Keywords||viral myocarditis Coxsackievirus group B type3 Th17 17β-estradiol sex differences|
Viral myocarditis (VMC) is a kind of clinical common infectious diseases ofcardiovascular system. Coxsackievirus group B type3(CVB3) infection is thepredominantly causative reason of VMC, has become one of the main reasons of suddendeath in young people. Sex-related differences in myocarditis susceptibilty are quiteobvious in adults. The incidence of VMC in men is about twice as likely as women andCVB3infection also causes severe myocarditis in male but not female mice.In our study, we explored the role of Th17in the process of viral myocarditisinCVB3-infected male and female mice. Infected mice showed obvious body weight lose,significantly increased serum CK level, a serological index of myocardial injury, anddiffuse and dramatical inflammation and necrosis in heart. Meanwhile, the morbidity ofmyocarditis in male mice was also significantly increased compared to female mice,indicating its much higher sensibility to VMC, and this distint was not attributed to theirdifferent virus-infection sensibility.Next, we further analysis the related cytokine profile of CD4+T subsets. The resultsshowed the expression of IL-17was increased significantly in male, FACS resultsindicated that compared with the0.92%of Th17in female, the percentage of Th17inmale reached as high as2.34%,and this increase of Th17percentage exhibited in avirus-dose dependent way. Then we elaborated analyzed the correlation of Th17percentage and the severity of VMC, as results showed that the higher percentage ofTh17cells, the higher severity of VMC, suggesting a obvious positive correlation. Wealso detected the kinetic changes of Th17percentages and found that the percentages ofsplenic Th17increased on day5post infection, and climbed to2.5%on day7. TheDynamic change curve highly in coincidence with the VMC progress, and the index ofweight loss and myocarditis score correlated to the severity of VMC, r2of the latter reach up to0.78. The aboved results fully indicated that Th17played an important rolein the different sexual susceptibity to VMC.Futher more, we detailedly campared the expressions of cytokines andtranscription factor involved in Th17develop ment and differentiation in CVB3-infectedmale and female mice. Results showed that no difference was evidenced in normal maleand female mice, but once CVB3infection, the expression of IL-6, IL-21, IL-22,RORγt,RORα significantly upregulated in male compared to female, indicated that theimmune microenvironment in male benefited Th17cell development. Next, we explorethe possible role of sex hormone in differential induction of Th17. CVB3-infected malemice were given17β-estradiol and the Th17percentage was measured. Compared withcontrol group, estrogen-treated mice possessed much fewer splenic Th17, thepercentages drop3.3fold. Meanwhile myocardial inflammatory infiltration and necrosissignificantly alleviated compared to control, survival rate increased from30%to80%.These results indicated us estrogen may protect VMC by inhibiting Th17.However, when female mice were treated testosterone, no robust change of Th17percentage was showed, and no improvement of VMC was evidenced, suggesting noeffects of testosterone on Th17induction and VMC severity.Our study not noly help to explore the important role of Th17cells in VMC, clarifythe moleculer mechanism of sex different induction, but ralso shed some light on thedevelopment of novel preventive and therapeutic strategies for viral myocarditis.