Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice
Jing Ye,
Yuan Wang,
Yao Xu,
Zhen Wang,
Ling Liu,
Menglong Wang,
Di Ye,
Jishou Zhang,
Zicong Yang,
Yingzhong Lin,
Qingwei Ji,
Jun Wan
Affiliations
Jing Ye
Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China; Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Yuan Wang
Department of Thyroid Breast Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
Yao Xu
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Zhen Wang
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Ling Liu
Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
Menglong Wang
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Di Ye
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Jishou Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
Zicong Yang
Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
Yingzhong Lin
Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China; Corresponding author.
Qingwei Ji
Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China; Corresponding author.
Jun Wan
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, China; Corresponding author.
Several interleukin (IL) family members have been demonstrated to be involved in doxorubicin (DOX)-induced cardiac injury. This study aimed to investigate the role of IL-22 in DOX-induced cardiac injury and explore its possible mechanisms. In this study, mice were given DOX, and the cardiac expression and sources of IL-22 were determined. Then, IL-22 was knocked out to observe the effects on DOX-induced cardiac injury in mice. In addition, the p38 mitogen-activated protein kinase (MAPK) pathway was inhibited, macrophages were depleted and adoptively transferred, and Fizz3 was up-regulated in mice to explore the mechanisms. The results showed that cardiac IL-22 expression was significantly increased by DOX treatment and was mostly derived from cardiac macrophages. IL-22 knockout significantly reduced cardiac vacuolization and the expression of cardiomyocyte injury markers in both serum and left ventricular tissue and improved cardiac function in DOX-treated mice. In addition, IL-22 knockout reversed DOX-induced cardiac M1 macrophage/M2 macrophage imbalance, reduced oxidative stress and protected against cardiomyocyte apoptosis. p38 MAPK pathway inhibition with SB203580 and macrophage depletion further alleviated the above effects in DOX-treated IL-22-knockout mice. The effects were stronger IL-22-knockout mice with adoptive transfer of WT macrophages than in those with adoptive transfer of IL-22-knockout macrophages. Furthermore, increasing the expression of Fizz3 reduced cardiomyocyte apoptosis and alleviated cardiac dysfunction. Our results may suggest that IL-22 knockout alleviate DOX-induced oxidative stress and cardiac injury by inhibiting macrophage differentiation and thereby increasing the expression of Fizz3. Reductions in IL-22 expression may be beneficial for clinical chemotherapy in tumor patients.
