Interleukin-22 deficiency alleviates doxorubicin-induced oxidative stress and cardiac injury via the p38 MAPK/macrophage/Fizz3 axis in mice

Abstract

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.

Interleukin‐9 deficiency affects lipopolysaccharide‐induced macrophage‐related oxidative stress and myocardial cell apoptosis via the Nrf2 pathway both in vivo and in vitro

“…There is increasing evidence that Møs are one of the most important sources of oxidative stress‐related substances. In addition, Mø differentiation is closely related to oxidative stress levels, and M1 Mø differentiation can significantly exacerbate oxidative stress, while M2 Mø differentiation can significantly reduce oxidative stress 35–37 . The Nrf2 pathway is the most important pathway that regulates oxidative stress in a variety of complex pathological injury factors 24,38,39 .…”

Anti-Interleukin-16-Neutralizing Antibody Attenuates Cardiac Inflammation and Protects against Cardiac Injury in Doxorubicin-Treated Mice

“…In addition to mediating an immune response, these immune cells can also release a large number of inflammatory factors, including IFN, transforming growth factor, chemokines, and ILs [22][23][24]. Multiple ILs, including IL-6, IL-12, and IL-22, are primarily secreted by activated immune cells and are rarely or not secreted by nonimmune cells [25][26][27]. Unlike these ILs, large amounts of IL-16 are secreted by both immune cells and cells [5][6][7].…”

“…Recently, Ye et al reported that increased activation of the p65 pathway significantly increased M1 macrophage differentiation in both Ang II-infused and DOX-induced mice [26,27]. Nuclear p-p65 but not total p-p65 regulates the differentiation and inflammatory response of macrophages [27][28][29][30]. To determine the effects of IL-16 on p65 pathway activation, the p-p65 levels in both the cytoplasm and nucleus were mea-sured.…”

Anti‐Interleukin‐16 Neutralizing Antibody Treatment Alleviates Sepsis‐Induced Cardiac Injury and Dysfunction via the Nuclear Factor Erythroid‐2 Related Factor 2 Pathway in Mice

“…Under normal physiological conditions, prooxidant and antioxidant substances maintain a dynamic balance, which is essential for the maintenance of normal physiological activities [ 28 , 29 ]. Under the action of doxorubicin, Ang II, and other external pathogenic factors, this stable equilibrium relationship is broken, as evidenced by reductions in the levels of antioxidants, including NRf2, HO-1, and SOD, and increases in the levels of oxygen-promoting substances, including Nox2, Nox4, and MDA [ 30 , 31 ]. To determine whether IL-16 is involved in sepsis-induced cardiac injury through the regulation of oxidative stress, pathways and markers related to oxidative stress were detected.…”