Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China; Department of Medical Department, Shanghai East Hospital, Tongji University, Shanghai, China.
Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai, China.
Int Immunopharmacol. 2018 Feb;55:263-271. doi: 10.1016/j.intimp.2017.12.030. Epub 2017 Dec 27.
Macrophage motility is vital in innate immunity, which contributes strategically to the defensive inflammation process. During bacterial infection, lipopolysaccharide (LPS) potently activates the migration of macrophages via the NF-κB/iNOS/c-Src signaling pathway. However, the downstream region of c-Src that participates in macrophage migration is unclear. EFhd2, a novel actin bundling protein, was evaluated for its role in LPS-stimulated macrophage migration in this study. We found that LPS stimulated the up-regulation, tyrosine phosphorylation and membrane translocation of EFhd2 in macrophages. The absence of EFhd2 inhibited the recruitment of macrophages in the lungs of LPS-induced septic mice. LPS-induced macrophage migration was neutralized by the deletion of EFhd2. EFhd2-mediated up-regulation of NFPs (including Rac1/Cdc42, N-WASP/WAVE2 and Arp2/3 complex) induced by LPS could be used to explain the role of EFhd2 in promoting actin polymerization. Furthermore, the purified EFhd2 could directly promote actin polymerization in vitro. Dasatinib, a c-Src specific inhibitor, inhibited the up-regulation of EFhd2 stimulated by LPS. Therefore, our study demonstrated that EFhd2 might be involved in LPS-stimulated macrophage migration, which provides a potential target for LPS-activated c-Src during macrophage mobilization.
巨噬细胞的迁移能力对于先天免疫至关重要，它对于防御性炎症反应具有战略意义。在细菌感染过程中，脂多糖（LPS）通过 NF-κB/iNOS/c-Src 信号通路强烈激活巨噬细胞的迁移。然而，c-Src 参与巨噬细胞迁移的下游区域尚不清楚。本研究评估了 EFhd2（一种新型肌动蛋白成束蛋白）在 LPS 刺激的巨噬细胞迁移中的作用。我们发现 LPS 刺激巨噬细胞中 EFhd2 的上调、酪氨酸磷酸化和膜转位。EFhd2 缺失抑制了 LPS 诱导的败血症小鼠肺部巨噬细胞的募集。EFhd2 的缺失中和了 LPS 诱导的巨噬细胞迁移。EFhd2 介导的 LPS 诱导的 NFPs（包括 Rac1/Cdc42、N-WASP/WAVE2 和 Arp2/3 复合物）的上调可以用来解释 EFhd2 在促进肌动蛋白聚合中的作用。此外，纯化的 EFhd2 可以在体外直接促进肌动蛋白聚合。c-Src 特异性抑制剂达沙替尼抑制 LPS 刺激的 EFhd2 上调。因此，我们的研究表明 EFhd2 可能参与 LPS 刺激的巨噬细胞迁移，这为 LPS 激活的 c-Src 在巨噬细胞动员期间提供了一个潜在的靶标。
