Rationale: Clinical application of doxorubicin (DOX) is limited by its toxic cardiovascular side effects. Our previous study found that toll-like receptor (TLR) 5 deficiency attenuated cardiac fibrosis in mice. However, the role of TLR5 in DOX-induced cardiotoxicity remains unclear./nMethods: To further investigate this, TLR5-deficient mice were subjected to a single intraperitoneal injection of DOX to mimic an acute model./nResults: Here, we reported that TLR5 expression was markedly increased in response to DOX injection. Moreover, TLR5 deficiency exerted potent protective effects against DOX-related cardiac injury, whereas activation of TLR5 by flagellin exacerbated DOX injection-induced cardiotoxicity. Mechanistically, the effects of TLR5 were largely attributed to direct interaction with spleen tyrosine kinase to activate NADPH oxidase (NOX) 2, increasing the production of superoxide and subsequent activation of p38. The toxic effects of TLR5 activation in DOX-related acute cardiac injury were abolished by NOX2 deficiency in mice. Our further study showed that neutralizing antibody-mediated TLR5 depletion also attenuated DOX-induced acute cardiotoxicity./nConclusion: These findings suggest that TLR5 deficiency attenuates DOX-induced cardiotoxicity in mice, and targeting TLR5 may provide feasible therapies for DOX-induced acute cardiotoxicity.

中文翻译：

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Toll样受体5缺乏症减少了阿霉素诱导的小鼠急性心脏毒性

原理：阿霉素（DOX）的临床应用受到其毒性心血管副作用的限制。我们之前的研究发现，Toll样受体（TLR）5缺乏症可减轻小鼠的心脏纤维化。然而，TLR5在DOX诱导的心脏毒性中的作用仍不清楚。/n方法：为了进一步研究这一点，对TLR5缺陷小鼠进行了一次腹膜内DOX模仿以模拟急性模型。在这里，我们报告说，响应DOX注射，TLR5表达明显增加。而且，TLR5缺乏对DOX相关的心脏损伤具有有效的保护作用，而鞭毛蛋白激活TLR5则加剧了DOX注射引起的心脏毒性。从机理上讲，TLR5的作用主要归因于与脾酪氨酸激酶的直接相互作用，以激活NADPH氧化酶（NOX）2，从而增加了超氧化物的产生并随后激活了p38。小鼠NOX2缺乏消除了TLR5激活在DOX相关急性心脏损伤中的毒性作用。我们的进一步研究表明，中和抗体介导的TLR5耗竭也减弱了DOX诱导的急性心脏毒性。/n结论： 这些发现表明，TLR5缺乏症减弱了DOX诱导的小鼠心脏毒性，而靶向TLR5可能为DOX诱导的急性心脏毒性提供可行的治疗方法。