Phagocytosis and Motility in Human Neutrophils is Competent but Compromised by Pharmacological Inhibition of Ezrin Phosphorylation
Phagocytosis and Motility in Human Neutrophils is Competent but Compromised by Pharmacological Inhibition of Ezrin Phosphorylation
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DOI：
10.2174/1874467211666180516100613
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发表时间：
2018-01-01
影响因子：
2.7
通讯作者：
Hallett, Maurice B.
中科院分区：
文献类型：
--
作者：
Roberts, Rhiannon E.;Elumalai, Geetha L.;Hallett, Maurice B.
背景和目的：Ezrin连接皮层细胞骨架和质膜，并在调节细胞形状变化中起作用。最近，已经显示NSC668394抑制其活性的关键步骤，即在苏氨酸567处的磷酸化。在中性粒细胞，另一个关键的调节步骤是钙离子介导的切割ezrin的calpain.Methods：在本文中，我们使用NSC668394作为一种药理学抑制剂来研究这两个步骤之间的相互作用，在调节中性粒细胞的形状的变化。具有NSC668394抑制的埃兹蛋白磷酸化的中性粒细胞保持吞噬和趋化能力。然而，吞噬作用轻微受损，趋化性不能维持较长时间。中性粒细胞所采取的特征性趋化形态也是异常的。虽然磷酸化ezrin起着次要的作用，在限制中性粒细胞的细胞形状的快速变化，抑制ezrin磷酸化NSC668394防止多个和长期的形状变化在延长chemotaxis.Conclusion：易感性的长期趋化抑制NSC668394可能指向一个有用的目标，抗炎治疗。抑制中性粒细胞对慢性炎症部位的趋化性而不损害其进行吞噬作用的能力是抗中性粒细胞治疗的一个非常受欢迎的效果。
Background and Objective: Ezrin links the cortical cytoskeleton to the plasma membrane and plays a role in regulating changes in cell shape. Recently, NSC668394 has been shown to inhibit a key step for its activity, i.e. phosphorylation at threonine 567. In neutrophils, another key regulatory step is the Ca2+-mediated cleavage of ezrin by calpain.Methods: In this paper, we use NSC668394 as a pharmacological inhibitor to investigate the interplay between these two steps in regulating changes in neutrophil shape.Results: NSC668394 reduced the amount of peripherally located ezrin in neutrophils, and increased Ca2+-dependent ezrin cleavage. Neutrophils with NSC668394-inhibited ezrin phosphorylation remained both phagocytic and chemotactically competent. However, phagocytosis was slightly impaired and chemotaxis could not be maintained over longer periods. The characteristic chemotactic morphology which neutrophils adopt was also aberrant. Although phosphorylation of ezrin plays a minor role in limiting the rapid changes in cell shape in neutrophils, inhibition of ezrin phosphorylation by NSC668394 prevented multiple and prolonged shape changes during extended chemotaxis.Conclusion: The susceptibility of prolonged chemotaxis to inhibition by NSC668394 may point to a useful target for anti-inflammatory therapy. Inhibition of neutrophil chemotaxis towards chronically inflamed sites without compromising their ability to undergo phagocytosis is a much sought after the effect of anti-neutrophil therapy.