Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation.

Jing Wang,Mingxing Xie,Qing Lv,Zhengyang Han,Yuman Li,Xiongwen Chen,Yihan Chen,Qiaofeng Jin,Dandan Chen,Tianshu Liu,Li Zhang

doi:10.3389/fphar.2020.613160

Abstract

Myocarditis is a type of inflammatory cardiomyopathy that has no specific treatment. Accumulating evidence suggests that Th17 cells play a prominent role in the pathogenesis of myocarditis. Interleukin-(IL)-6-mediated signal transducer and activation of transcription 3 (STAT3) signaling is essential for Th17 cell differentiation and secretion of inflammatory cytokines. Bazedoxifene inhibits IL-6/STAT3 signaling in cancer cells, but its effect on the Th17 immune response induced by myocarditis remains unknown. Here we explore the effect of Bazedoxifene on Th17 immune response and cardiac inflammation in a mouse model of experimental autoimmune myocarditis, which has been used to mimic human inflammatory heart disease. After eliciting an immune response, we found Bazedoxifene ameliorated cardiac inflammatory injury and dysfunction. Th17 cells and related inflammatory factors in splenic CD4+ T cells at day 14 and in the heart at day 21 were increased, which were reduced by Bazedoxifene. Furthermore, Bazedoxifene could regulate autophagy induction in polarized Th17 cells. In conclusion, Bazedoxifene affected STAT3 signaling and prevented cardiac inflammation deterioration, so may provide a promising therapeutic strategy for the treatment of experimental autoimmune myocarditis (EAM).

Highlights

Myocarditis is an inflammatory cardiomyopathy that leads to acute heart failure, dilated cardiomyopathy, and sudden death (Bracamonte-Baran and Cihakova, 2017)
As shown by histopathological analysis, Bazedoxifene decreased inflammatory cell infiltration detected by immunostaining of CD45 (Figure 1D) and IL-6 in the heart tissue of experimental autoimmune myocarditis (EAM) mice (Figure 1D)
Data are presented as mean ± SEM; LVID, left ventricular internal dimension. aP

Summary

Introduction

Myocarditis is an inflammatory cardiomyopathy that leads to acute heart failure, dilated cardiomyopathy, and sudden death (Bracamonte-Baran and Cihakova, 2017). Current treatments for myocarditis include supportive therapy and immunosuppressive therapy, but the effectiveness of these treatments is not yet clear (Jensen and Marchant, 2016). There is a need to further understand the mechanism of myocarditis and explore novel pharmacologic treatments in order to ameliorate cardiac injury and help patients to survive. The immune response involved in the progression of experimental autoimmune myocarditis (EAM) is complex. Studies have suggested a critical role for CD4+ T cells in the development of EAM (Błyszczuk, 2019). The conventional view is that autoimmune diseases are primarily dependent on Th1 and Th2 cells (Nindl et al, 2012). Th17 cells have been identified as playing a crucial

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