Theranostics 2018; 8(16):4552-4562. doi:10.7150/thno.24723 This issue

Research Paper

Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction

Ting-Ting Tang1,2, Yuan-Yuan Li1,2, Jing-Jing Li1,2, Ke Wang1,2, Yue Han1,2, Wen-Yong Dong1,2, Zheng-Feng Zhu1,2, Ni Xia1,2, Shao-Fang Nie1,2, Min Zhang1,2, Zhi-Peng Zeng1,2, Bing-Jie Lv1,2, Jiao Jiao1,2, Heng Liu3, Zong-Shu Xian3, Xiang-Ping Yang4, Yu Hu5,6, Yu-Hua Liao1,2, Qing Wang7, Xin Tu7, Ziad Mallat8, Yu Huang9, Guo-Ping Shi10, Xiang Cheng1,2✉

1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2. Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan 430022, China
3. Generon Corporation, Building 9, 720 Cai Lun Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, China
4. Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
5. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China
6. Targeted Biotherapy Key Laboratory of Ministry of Education, Wuhan 430022, China
7. Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, China
8. Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, CB20 SZ, UK
9. Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China
10. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
T.T.Tang, Y.Y. Li, J.J. Li and K. Wang contributed equally to this study.

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Citation:
Tang TT, Li YY, Li JJ, Wang K, Han Y, Dong WY, Zhu ZF, Xia N, Nie SF, Zhang M, Zeng ZP, Lv BJ, Jiao J, Liu H, Xian ZS, Yang XP, Hu Y, Liao YH, Wang Q, Tu X, Mallat Z, Huang Y, Shi GP, Cheng X. Liver-heart crosstalk controls IL-22 activity in cardiac protection after myocardial infarction. Theranostics 2018; 8(16):4552-4562. doi:10.7150/thno.24723. Available from https://www.thno.org/v08p4552.htm

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Abstract

Graphic abstract

Interleukin (IL)-22 regulates tissue inflammation and repair. Here we report participation of the liver in IL-22-mediated cardiac repair after acute myocardial infarction (MI).

Methods: We induced experimental MI in mice by ligation of the left ascending artery and evaluated the effect of IL-22 on post-MI cardiac function and ventricular remodeling.

Results: Daily subcutaneous injection of 100 µg/kg mouse recombinant IL-22 for seven days attenuated adverse ventricular remodeling and improved cardiac function in mice at 28 days after left anterior descending coronary artery ligation-induced MI. Pharmacological inhibition of signal transducer and activator of transcription (STAT3) muted these IL-22 activities. While cardiomyocyte-selective depletion of STAT3 did not affect IL-22 activities in protecting post-MI cardiac injury, hepatocyte-specific depletion of STAT3 fully muted these IL-22 cardioprotective activities. Hepatocyte-derived fibroblast growth factor (FGF21) was markedly increased in a STAT3-dependent manner following IL-22 administration and accounted for the cardioprotective benefit of IL-22. Microarray analyses revealed that FGF21 controlled the expression of cardiomyocyte genes that are involved in cholesterol homeostasis, DNA repair, peroxisome, oxidative phosphorylation, glycolysis, apoptosis, and steroid responses, all of which are responsible for cardiomyocyte survival.

Conclusions: Supplementation of IL-22 in the first week after acute MI effectively prevented left ventricular dysfunction and heart failure. This activity of IL-22 involved crosstalk between the liver and heart after demonstrating a role of the hepatic STAT3-FGF21 axis in IL-22-induced post-MI cardiac protection.

Keywords: IL-22, myocardial infarction, liver-heart crosstalk, FGF21