Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, United States.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States.
Front Endocrinol (Lausanne). 2021 Mar 10;12:565981. doi: 10.3389/fendo.2021.565981. eCollection 2021.
A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.
越来越多的证据表明，中性粒细胞是在 1 型糖尿病（T1D）中功能性β细胞发生淋巴细胞驱动损伤之前，最早积聚在胰腺内的主要白细胞群体之一。在人类中，来自 T1D 已故供体的胰腺表现出明显的中性粒细胞积聚。我们展示了一个以前未知的炎症变化时间过程，该过程伴随着非肥胖型糖尿病（NOD）小鼠品系胰腺中中性粒细胞和中性粒细胞弹性蛋白酶的积累，早在 2 周龄时就出现了。我们证实了之前在 NOD 小鼠中发现的中性粒细胞早在 2 周龄时就开始积聚的发现。我们还观察到在此期间，同一时间内中性粒细胞弹性蛋白酶的表达也同时增加。我们还在这段时间内检测到主要存在于胰腺外分泌组织中的中性粒细胞细胞外陷阱（NET）的组成部分，以及早在 2 周龄时就出现的血管病理学标志物。在年龄和性别匹配的 C57BL/6 小鼠中，胰腺内没有这些特征。当我们用髓过氧化物酶和中性粒细胞弹性蛋白酶抑制剂单独或联合处理 NOD 小鼠时，我们无法以任何不同于未治疗对照小鼠的方式阻止向高血糖的进展。我们的数据证实并增加了证据，证明在易患 T1D 的小鼠的胰腺中存在中性粒细胞的积累，并且还提供了有关涉及胰腺血管的其他病理机制的新见解，直到现在，这些机制尚未在这些小鼠的胰腺中发现。然而，抑制在激活的中性粒细胞中表达的关键中性粒细胞酶并不能预防糖尿病。这些发现增加了支持中性粒细胞在胰腺内早期病理学建立中发挥作用的数据，独立于淋巴细胞浸润的时间，并且更早。然而，它们也表明，仅抑制中性粒细胞，单独作用于髓过氧化物酶和中性粒细胞弹性蛋白酶，而没有其他效应细胞，不足以改变自身免疫性糖尿病的自然病程，至少在 NOD 疾病模型中是如此。
