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首页> 外文期刊>International Journal of Experimental Pathology >Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice
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Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice

机译：抑制谷氨酰胺酰环化酶可减轻CCL2介导的小鼠非酒精性脂肪肝疾病的炎症

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Inflammation is an integral part of non-alcoholic fatty liver disease (NAFLD), the most prevalent form of hepatic pathology found in the general population. In this context, recently we have examined the potential role of Glutaminyl Cyclases (QC and isoQC), and their inhibitors, in the maturation of chemokines, for example, monocyte chemoattractant protein 1 (MCP-1, CCL2), to generate their bioactive conformation. Catalysis by isoQC leads to the formation of an N-terminal pyroglutamate residue protecting CCL2 against degradation by aminopeptidases. This is of importance because truncated forms possess a reduced potential to attract immune cells. Since liver inflammation is characterized by the up-regulation of different chemokine pathways, and within this CCL2 is known to be a prominent example, we hypothesised that application of QC/isoQC inhibitors may alleviate liver inflammation by destabilizing CCL2. Therefore, we investigated the role of QC/isoQC inhibition, in comparison with the angiotensin receptor blocker Telmisartan, during development of pathology in a mouse model of non-alcoholic fatty liver disease. Application of a QC/isoQC inhibitor led to a significant reduction in circulating alanine aminotransferase and NAFLD activity score accompanied by an inhibitory effect on hepatocyte ballooning. Further analysis revealed a specific reduction of inflammation by decreasing the number of F4/80-positive macrophages, which is in agreement with the proposed CCL2-related mechanism of action of QC/isoQC inhibitors. Finally, QC/isoQC inhibitor application attenuated liver fibrosis as characterized by reduced collagen deposition in the liver parenchyma. Thus in conclusion, QC/isoQC inhibitors are a promising novel class of anti-non-alcoholic steatohepatitis drugs which have a comparable disease-modifying effect to that of Telmisartan, which is probably mediated via specific interference with a comparable monocyte/macrophage infiltration that occurs under inflammatory conditions.
机译：炎症是非酒精性脂肪肝疾病（NAFLD）不可或缺的一部分，NAFLD是普通人群中最常见的肝病理形式。在这种情况下，最近我们研究了谷氨酰胺基环化酶（QC和isoQC）及其抑制剂在趋化因子（例如单核细胞趋化蛋白1（MCP-1，CCL2））成熟中的潜在作用，以产生其生物活性构象。 。 isoQC催化导致形成N末端焦谷氨酸残基，保护CCL2免受氨基肽酶降解。这是重要的，因为截短形式具有降低的吸引免疫细胞的潜力。由于肝脏炎症的特征在于不同趋化因子途径的上调，并且已知该CCL2是一个突出的例子，因此我们假设QC / isoQC抑制剂的应用可以通过使CCL2不稳定来减轻肝脏炎症。因此，我们研究了在非酒精性脂肪肝疾病小鼠模型中病理发展过程中，与血管紧张素受体阻滞剂替米沙坦相比，QC / isoQC抑制的作用。 QC / isoQC抑制剂的应用导致循环丙氨酸氨基转移酶和NAFLD活性评分显着降低，并伴有对肝细胞膨胀的抑制作用。进一步的分析显示，通过减少F4 / 80阳性巨噬细胞的数量，炎症的特异性减少，这与QC / isoQC抑制剂的CCL2相关作用机制相一致。最后，QC / isoQC抑制剂的应用减轻了肝纤维化，其特征是减少了肝实质中胶原蛋白的沉积。因此，总而言之，QC / isoQC抑制剂是一种有前途的新型非酒精性脂肪性肝炎药物，其疾病改良作用与替米沙坦相当，这可能是通过对发生的可比的单核细胞/巨噬细胞浸润的特异性干扰介导的。在炎症条件下。

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