Department of Clinical Sciences, College of Veterinary Medicine, North Caroline State University, Raleigh, North Carolina, USA.
Am J Respir Cell Mol Biol. 2010 May;42(5):586-94. doi: 10.1165/rcmb.2008-0394OC. Epub 2009 Jul 2.
Neutrophil migration into infected tissues is essential for host defense, but products of activated neutrophils can be quite damaging to host cells. Neutrophil influx into the lung and airways and resultant inflammation characterizes diseases such as chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. To migrate, neutrophils must reorganize the actin cytoskeleton to establish a leading edge pseudopod and a trailing edge uropod. The actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) has been shown to bind and cross-link actin in a variety of cell types and to co-localize with F-actin in the leading edge lamellipodium of migrating fibroblasts. The hypothesis that MARCKS has a role in the regulation of neutrophil migration was tested using a cell-permeant peptide derived from the MARCKS myristoylated aminoterminus (MANS peptide). Treatment of isolated human neutrophils with MANS significantly inhibited both their migration and beta2 integrin-dependent adhesion in response to N-formyl-methionyl-leucyl-phenylalanine (fMLF), IL-8, or leukotriene (LT)B(4). The IC(50) for fMLF-induced migration and adhesion was 17.1 microM and 12.5 microM, respectively. MANS significantly reduced the F-actin content in neutrophils 30 seconds after fMLF stimulation, although the peptide did not alter the ability of cells to polarize or spread. MANS did not alter fMLF-induced increases in surface beta2 integrin expression. These results suggest that MARCKS, via its myristoylated aminoterminus, is a key regulator of neutrophil migration and adhesion.
中性粒细胞向感染组织的迁移对于宿主防御至关重要，但活化的中性粒细胞产物可能对宿主细胞造成严重损害。中性粒细胞涌入肺部和气道，并导致炎症，这是慢性阻塞性肺疾病、支气管扩张和囊性纤维化等疾病的特征。为了迁移，中性粒细胞必须重新组织肌动蛋白细胞骨架，以建立一个前缘伪足和一个后缘尾足。已经表明，酰化的丙氨酸丰富的 C 激酶底物（MARCKS）结合肌动蛋白并在多种细胞类型中交联肌动蛋白，并与迁移成纤维细胞前缘片状伪足中的 F-肌动蛋白共定位。MARCKS 在调节中性粒细胞迁移中的作用的假设通过使用源自 MARCKS 酰化氨基末端的细胞渗透性肽（MANS 肽）进行了测试。用 MANS 处理分离的人中性粒细胞，可显著抑制其迁移和β2 整合素依赖性粘附，对 N-甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸（fMLF）、IL-8 或白三烯（LT）B（4）的反应。fMLF 诱导的迁移和粘附的 IC（50）分别为 17.1 μM 和 12.5 μM。MANS 在 fMLF 刺激后 30 秒内显著降低中性粒细胞中的 F-肌动蛋白含量，尽管该肽不改变细胞极化或扩散的能力。MANS 不改变 fMLF 诱导的表面β2 整合素表达增加。这些结果表明，MARCKS 通过其酰化氨基末端是中性粒细胞迁移和粘附的关键调节剂。
