Departments of 1 Biomolecular Chemistry and.
Am J Respir Cell Mol Biol. 2014 Mar;50(3):654-64. doi: 10.1165/rcmb.2013-0181OC.
The experiments described herein define a unique program of polarization of suspended human eosinophils stimulated with IL-5 family cytokines. We found that eosinophil granules and the nucleus move in opposite directions to form, respectively, a granular compartment and the nucleopod, a specialized uropod occupied by the nucleus and covered with adhesion receptors, including P-selectin glycoprotein ligand-1, CD44, and activated αMβ2 integrin. Ligated IL-5 family receptors localize specifically at the tip of the nucleopod in proximity to downstream signaling partners Janus tyrosine kinase 2, signal transducer and activator of transcription-1 and -5, and extracellular signal-regulated kinase. Microscopy and effects of cytochalasin B and nocodazole indicate that remodeling of filamentous actin and reorientation of the microtubule network are required for eosinophil polarization and nucleopod formation. IL-5 induces persistent polarization and extracellular signal-regulated kinase redistribution that are associated with eosinophil priming, a robust response on subsequent stimulation with N-formyl-methionyl-leucyl-phenylalanine. Global reorganization of cytoskeleton, organelles, adhesion receptors, and signaling molecules likely facilitates vascular arrest, extravasation, migration, granule release, and survival of eosinophils entering inflamed tissues from the bloodstream.
本文所述的实验定义了一种独特的人嗜酸性粒细胞悬浮液极化方案，由白细胞介素-5 家族细胞因子刺激。我们发现嗜酸性粒细胞颗粒和细胞核向相反的方向移动，分别形成颗粒区室和核足，这是一种特殊的足状突起，被核占据并覆盖着粘附受体，包括 P-选择素糖蛋白配体-1、CD44 和激活的αMβ2 整合素。连接的白细胞介素-5 家族受体在核足的尖端特异性定位，靠近下游信号转导伙伴 Janus 酪氨酸激酶 2、信号转导和转录激活因子-1 和-5 以及细胞外信号调节激酶。显微镜观察和细胞松弛素 B 和诺考达唑的作用表明，丝状肌动蛋白的重塑和微管网络的重定向是嗜酸性粒细胞极化和核足形成所必需的。白细胞介素-5 诱导持续的极化和细胞外信号调节激酶再分布，这与嗜酸性粒细胞的初始激活有关，在随后用 N-甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸刺激时会产生强烈的反应。细胞骨架、细胞器、粘附受体和信号分子的整体重排可能有助于血管阻滞、渗出、迁移、颗粒释放以及从血流进入炎症组织的嗜酸性粒细胞的存活。
