Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release
Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release
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DOI：
10.3389/fimmu.2019.03021
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发表时间：
2020-01-15
影响因子：
7.3
通讯作者：
Kolaczkowska, Elzbieta
中科院分区：
文献类型：
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作者：
Cichon, Iwona;Ortmann, Weronika;Kolaczkowska, Elzbieta
中性粒细胞胞外陷阱（NETs）参与病理紊乱，其释放与许多疾病直接相关。通过活体显微镜（IVM），我们之前发现NETs也有助于全身性炎症的病理，并强烈沉积在肝窦中。自NET发现以来的十多年里，人们对它们形成的代谢或微环境方面仍然知之甚少。铜是许多生物过程中必不可少的重要微量元素，尽管其过量可能具有细胞毒性；因此，铜的水平受到铜转运atp酶、ATP7A和ATP7B等因素的严格控制。通过IVM，我们分别在两种铜过量或缺乏的小鼠模型，Wilson （ATP7B突变体）和Menkes （ATP7A突变体）上研究了铜对肝血管内毒素血症时NET形成的影响。在这里，我们表明，尽管中性粒细胞在体外测试中释放NET的内在能力没有改变，但在全身性炎症期间，各自的ATP7突变导致NET释放减少。在Menkes病小鼠中，体内效应主要是由于肝脏中性粒细胞浸润减少，因为亚慢性铜缺乏的未突变小鼠在内毒素血症期间释放的net甚至比对照组更多，而在Wilson病小鼠中，过量的铜直接降低了释放net的能力，这一点在与外源性铜和铜螯合剂共培养的分离中性粒细胞的离体研究中得到进一步证实。综上所述，该研究扩展了我们对微环境因素如何影响NET释放的理解，表明铜不是NET释放的先决条件，但其过量会影响中性粒细胞的陷阱铸造。
Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.