Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

Abstract

Previous studies have demonstrated that interleukins (ILs) are closely associated with doxorubicin (DOX)-induced cardiac injury. IL-5 is an important member of the IL family, and this study was performed to investigate whether IL-5 affects DOX-induced cardiac injury and its underlying mechanisms. The cardiac IL-5 expression was first detected and the results showed that cardiac IL-5 levels were significantly lower in DOX-treated mice, and IL-5 was mainly derived from cardiac macrophage (Mø). In addition, some DOX-treated mice received an injection of anti-IL-5-neutralizing antibody (nAb), and we found that treatment with a mouse anti-IL-5 nAb significantly upregulated the levels of myocardial injury markers, aggravated cardiac dysfunction, increased M1 macrophage (Mø1) and decreased M2 macrophage (Mø2) differentiation, and promoted apoptotic marker expression. Furthermore, the effect of mouse IL-5 nAb on DOX-induced Mø differentiation and its role on mouse cardiomyocyte (MCM) cells apoptosis were detected in vitro, and the results exhibited that mouse IL-5 nAb promoted Mø1 differentiation but inhibited Mø2 differentiation in vitro and alleviated apoptosis in MCM cells. Our results found a mouse anti-IL-5 nAb-aggravated DOX-induced cardiac injury and dysfunction by alleviating the inflammatory response and myocardial cell apoptosis. (L. L.), and yingzhonglin@126.com (Y. L.) Abbreviations: ANOVA, analysis of variance; Arg-1, arginase-1; CK-MB, creatine kinase myocardial-bound; DOX, doxorubicin; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin; HR, heart rate; IFN-γ, interferon γ; ILs, interleukins; IL-5R, IL-5 receptors; iNOS, inducible nitric oxide synthase; JAK1/2, Janus Kinase 1/2; LDH, lactate dehydrogenase; LV, left ventricle; LVEF, left ventricle ejection fraction; LVEDP, left ventricular enddiastolic pressure; LVFS, left ventricle fractional shortening; LVSP, left ventricular systolic pressure; Mø, macrophage; MCMs, mouse cardiomyocytes; Mø1, M1 macrophage; Mø2, M2 macrophage; nAb, neutralizing antibody; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; STAT1/5, signal transducer and activator of transcription 1/5; SMCs, smooth muscle cells; SD, standard deviation; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling; WT, wild-type; +dP/dt max, maximal slope of the systolic pressure increment; −dP/dt max, maximal slope of the diastolic pressure decrement

Interleukin‐5 deletion promotes sepsis‐induced M1 macrophage differentiation, deteriorates cardiac dysfunction, and exacerbates cardiac injury via the NF‐κB p65 pathway in mice

“…To examine the expression of IL‐5 in sepsis, IL‐5 expression in mice treated with LPS or received cecal ligation surgery was measured, and the results showed that both treatment with LPS and cecal ligation decreased IL‐5 expression, which suggests that IL‐5 participates in the progression of sepsis. In addition, previous studies reported that inflammation‐mediated substances, such as doxorubicin, Ang II, and a high‐fat diet, decreased IL‐5 expression in mice 13–16 . Our data showed that both LPS and cecal ligation decreased IL‐5 expression in mice.…”

“…4,16,28,33 M1 macrophages can release a variety of important pro-inflammatory factors, which are closely related to myocardial cell apoptosis, a similar effect was also observed in sepsis. 4,5,16,28 After confirming that IL-5 deficiency promotes LPS-induced M1 macrophage differentiation in vitro, we determined whether myocardial cell apoptosis was mediated by the differentiation of M1 macrophages by coculturing myocardial cells with macrophages. The results showed that coculture with IL-5−/− macrophages significantly increased myocardial cell apoptosis after LPS administration and was significantly decreased by JSH-23 treatment.…”

“…Myocardial cells have poor tolerance for inflammatory substances, and an excessive inflammatory response is one of the most important reasons for myocardial cell apoptosis 4,16,28,33 . M1 macrophages can release a variety of important pro‐inflammatory factors, which are closely related to myocardial cell apoptosis, a similar effect was also observed in sepsis 4,5,16,28 .…”

“…24,25 IL-5 has been widely recognized as being involved in a variety of cardiovascular diseases, including acute cardiac injury and atherosclerosis, by regulating macrophage differentiation. [13][14][15][16] Although M2 macrophages can release antiinflammatory cytokines to protect against sepsis-induced tissue and organ injury and decreased M2 macrophages and M2 macrophage-related cytokines also exacerbate injury of tissues and organs, M1 macrophages are (c) The number of TUNEL-positive cardiac cells in each group was measured (400×). N = 5 in each group.…”

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

“…The interleukin (IL) family is a multifunctional cytokine family, several members of which have been reported to regulate DOX-induced acute cardiac injury in mice. In a recent study, neutralization of IL-5 was reported to promote the secretion of various cardiac cytokines and to reduce cardiac function in DOX-treated mice [ 5 ]. In a mouse model, overexpression of IL-10 by adeno-associated virus 1 (AAV-1) significantly reversed DOX-induced cardiotoxicity [ 6 ].…”