Walter-Brendel-Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Klinikum der Universität, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Haematologica. 2020 Jul;105(7):1845-1856. doi: 10.3324/haematol.2019.225722. Epub 2019 Nov 7.
Leukocyte recruitment into inflamed tissue is highly dependent on the activation and binding of integrins to their respective ligands, followed by the induction of various signaling events within the cell referred to as outside-in signaling. Src family kinases (SFK) are the central players in the outside-in signaling process, assigning them a critical role for proper immune cell function. Our study investigated the role of SFK on neutrophil recruitment using mice, which lack SFK expressed in neutrophils. We show that loss of SFK strongly reduces neutrophil adhesion and post-arrest modifications in a shear force dependent manner. Additionally, we found that in the absence of SFK, neutrophils display impaired Rab27a-dependent surface mobilization of neutrophil elastase, VLA3 and VLA6 containing vesicles. This results in a defect in neutrophil vascular basement membrane penetration and thus strongly impaired extravasation. Taken together, we demonstrate that SFK play a role in neutrophil post-arrest modifications and extravasation during acute inflammation. These findings may support the current efforts to use SFK-inhibitors in inflammatory diseases with unwanted neutrophil recruitment.
白细胞向炎症组织的募集高度依赖于整合素与其相应配体的激活和结合，随后细胞内发生各种被称为“外向信号”的信号转导事件。Src 家族激酶（SFK）是外向信号转导过程中的核心参与者，使它们在免疫细胞的正常功能中发挥关键作用。我们使用缺乏在中性粒细胞中表达的 SFK 的 小鼠研究了 SFK 在中性粒细胞募集中的作用。我们发现，SFK 的缺失以剪切力依赖的方式强烈减少中性粒细胞的黏附和逮捕后修饰。此外，我们发现，在缺乏 SFK 的情况下，中性粒细胞显示出 Rab27a 依赖性中性粒细胞弹性蛋白酶、包含 VLA3 和 VLA6 的囊泡的表面动员受损。这导致中性粒细胞对血管基底膜的穿透缺陷，从而严重削弱了渗出。总之，我们证明 SFK 在急性炎症期间的中性粒细胞逮捕后修饰和渗出中发挥作用。这些发现可能支持目前在炎症性疾病中使用 SFK 抑制剂来阻止不受欢迎的中性粒细胞募集的努力。
