Journal of Proteomics ( IF 2.8 ) Pub Date : 2020-05-27 , DOI: 10.1016/j.jprot.2020.103843 Maria Weigand 1 , Roxane L Degroote 1 , Barbara Amann 1 , Simone Renner 2 , Eckhard Wolf 3 , Stefanie M Hauck 4 , Cornelia A Deeg 1
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INSC94Y transgenic pigs develop a stable diabetic phenotype early after birth and therefore allow studying the influence of hyperglycemia on primary immune cells in an early stage of diabetes mellitus in vivo. Since immune response is altered in diabetes mellitus, with deviant neutrophil function discussed as one of the possible causes in humans and mouse models, we investigated these immune cells in INSC94Y transgenic pigs and wild type controls at protein level. A total of 2371 proteins were quantified by label-free LC-MS/MS. Subsequent differential proteome analysis of transgenic animals and controls revealed clear differences in protein abundances, indicating a deviant behavior of granulocytes in the diabetic state. Interestingly, abundance of myosin regulatory light chain 9 (MLC-2C) was increased 5-fold in cells of diabetic pigs. MLC-2C directly affects cell contractility by regulating myosin ATPase activity, can act as transcription factor and was also associated with inflammation. It might contribute to impaired neutrophil cell adhesion, migration and phagocytosis.
Our study provides novel insights into proteome changes in neutrophils from a large animal model for permanent neonatal diabetes mellitus and points to dysregulation of neutrophil function even in an early stage of this disease.
Data are available via ProteomeXchange with identifier PXD017274.
Significance
Our studies provide novel basic information about the neutrophil proteome of pigs and contribute to a better understanding of molecular mechanisms involved in altered immune cell function in an early stage diabetes. We demonstrate proteins that are dysregulated in neutrophils from a transgenic diabetic pig and have not been described in this context so far. The data presented here are highly relevant for veterinary medicine and have translational quality for diabetes in humans.
中文翻译：
来自转基因糖尿病猪模型的中性粒细胞的蛋白质组谱显示出明显的变化。
INS C94Y转基因猪出生后早期便表现出稳定的糖尿病表型，因此可以在体内早期研究高血糖对初次免疫细胞的影响。由于糖尿病患者的免疫反应发生了变化，嗜中性粒细胞功能异常被认为是人类和小鼠模型的可能原因之一，因此我们在INS C94Y中研究了这些免疫细胞蛋白水平的转基因猪和野生型对照。通过无标记LC-MS / MS定量分析了总共2371种蛋白质。随后对转基因动物和对照进行差异蛋白质组分析，发现蛋白质丰度存在明显差异，表明糖尿病状态下的粒细胞有异常行为。有趣的是，在糖尿病猪的细胞中，肌球蛋白调节性轻链9（MLC-2C）的丰度增加了5倍。MLC-2C通过调节肌球蛋白ATPase的活性直接影响细胞的收缩力，可以作为转录因子，还与炎症有关。它可能导致中性粒细胞粘附，迁移和吞噬功能受损。
我们的研究为永久性新生儿糖尿病的大型动物模型提供了中性粒细胞蛋白质组变化的新颖见解，并指出中性粒细胞功能失调甚至在该疾病的早期也是如此。
数据可通过ProteomeXchange获得，其标识符为PXD017274。
意义
我们的研究提供了有关猪中性粒细胞蛋白质组的新颖基本信息，有助于更好地了解早期糖尿病中与免疫细胞功能改变有关的分子机制。我们证明了从转基因糖尿病猪的嗜中性粒细胞中失调的蛋白质，到目前为止在此背景下尚未描述。此处提供的数据与兽药高度相关，并且对人类糖尿病具有翻译质量。
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