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

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

doi:10.3389/fphar.2020.613160

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

Front Pharmacol. 2021 Feb 10:11:613160. doi: 10.3389/fphar.2020.613160. eCollection 2020.

Authors

Jing Wang^{1

2}, Tianshu Liu^{1

2}, Xiongwen Chen³, Qiaofeng Jin^{1

2}, Yihan Chen^{1

2}, Li Zhang^{1

2}, Zhengyang Han^{1

2}, Dandan Chen^{1

2}, Yuman Li^{1

2}, Qing Lv^{1

2}, Mingxing Xie^{1

2}

Affiliations

¹ Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
³ Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, United States.

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).

Keywords: Th17 cell; autophagy; experimental autoimmune myocarditis; interleukin-6; signal transducer and activator of transcription 3.