IDO1 depletion induces an anti-inflammatory response in macrophages in mice with chronic viral myocarditis
IDO1 depletion induces an anti-inflammatory response in macrophages in mice with chronic viral myocarditis
复制标题
DOI：
10.1080/15384101.2019.1652471
复制
发表时间：
2019-08-16
期刊：
影响因子：
4.3
通讯作者：
Xu, Haiming
中科院分区：
文献类型：
--
作者：
Guo, Gongliang;Sun, Liqun;Xu, Haiming
慢性病毒性心肌炎（VMC）的两个主要特征是炎症和心肌无力，常导致扩张型心肌病或慢性心力衰竭。吲哚胺2，3-双加氧酶-1（IDO 1）可能在炎症性疾病的进展中发挥致病作用。因此，本研究通过腹腔注射柯萨奇病毒B3（CVB 3）建立小鼠VMC模型，探讨IDO 1在慢性VMC中的潜在作用。模型建立后，通过RT-qPCR和Western blot分析IDO 1的表达。IDO 1在CVB 3诱导的VMC中表达上调。然后，为了阐明IDO 1在VMC中的潜在作用，分离巨噬细胞并用IDO 1或IDO 1抑制剂（1-MT）的过表达质粒处理。之后，将这些转染的巨噬细胞与正常心肌细胞共培养，随后测量炎症因子并评价心肌细胞损伤。观察到IDO 1的过表达显著提高了白细胞介素（IL）-6、IL-1 β和肿瘤坏死因子-α（TNF-α）的水平，以及乳酸脱氢酶（LDH）活性和丙二醛（MDA）含量。相比之下，1-MT处理巨噬细胞逆转IDO 1对心肌细胞损伤的促进作用。共培养实验显示IDO 1过表达对心肌细胞有损伤作用，1-MT处理后可减轻IDO 1的损伤。总之，本研究的关键发现提供了证据，表明1-MT介导的IDO 1抑制可能会减少巨噬细胞中的炎症反应，从而改善VMC小鼠的心肌细胞损伤。
Inflammation and myocardial weakness, two major hallmarks of chronic viral myocarditis (VMC), often lead to dilated cardiomyopathy or chronic heart failure. It has been reported that indoleamine 2,3-dioxygenase-1 (IDO1) may play a pathogenic role in the progression of inflammatory diseases. Hence, the study is set out to investigate the potential role of IDO1 in chronic VMC by establishing a mouse model of VMC by intraperitoneally injected with coxsackievirus B3 (CVB3). After model establishment, the expression of IDO1 was determined by RT-qPCR and Western blot analysis. IDO1 was identified as an up-regulated gene in CVB3-induced VMC. Then, in order to elucidate the potential role of IDO1 in VMC, macrophages were isolated and treated with the overexpression plasmid of IDO1 or IDO1 inhibitor (1-MT). After that, these transfected macrophages were co-cultured with normal cardiomyocytes, followed by measurement of inflammatory factors and evaluation of cardiomyocyte injury. The overexpression of IDO1 was observed to significantly enhance the levels of interleukin (IL)-6, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha), as well as lactate dehydrogenase (LDH) activity and malondialdehyde (MDA) content. By contrast, the treatment of 1-MT in macrophages reversed the promoting effects of IDO1 on cardiomyocyte injury. Co-culture experiment showed that overexpressed IDO1 impaired cardiomyocyte, which was alleviated upon treatment of 1-MT. Taken together, the key findings of the present study provide evidence that 1-MT-mediated IDO1 suppression could potentially reduce inflammatory response in macrophages and consequently ameliorate cardiomyocyte injury in mice with VMC.