Human Macrophages Utilize the Podosome Formin FMNL1 for Adhesion and Migration.
Human Macrophages Utilize the Podosome Formin FMNL1 for Adhesion and Migration.
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DOI：
10.4236/cellbio.2015.41001
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Blystone SD
中科院分区：
文献类型：
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作者：
Miller MR;Blystone SD
巨噬细胞在检测、调节和解决免疫危机中起着至关重要的作用，需要通过复杂的细胞外基质迁移。不必要的巨噬细胞炎症活动增强肾脏疾病、类风湿性关节炎和移植排斥。肌动蛋白细胞骨架的适当重塑，特别是在粘附结构，是必不可少的巨噬细胞的易位。巨噬细胞形成富含肌动蛋白的粘连，称为“足体”，使它们能够与基质接触，以牵引通过间质组织。巨噬细胞表达多种formins，包括FMNL 1，Dia 1和Fhod 1，有可能影响参与迁移的肌动蛋白重塑。形成蛋白是一个蛋白质家族，其最为人所知的是通过成核、伸长、成束和/或切断肌动蛋白丝来修饰肌动蛋白细胞骨架。在这项研究中，我们证明，pIFMNL 1是一个关键的调节器的podosomes和所需的正常巨噬细胞迁移。此外，这是第一项证明由特异性沉默引起的原代人类细胞迁移缺陷的研究。药理学上抑制所有的细胞因子活性导致足体形成和正常巨噬细胞迁移的显著减少。此外，FMNL 1的靶向抑制导致巨噬细胞迁移的减少，类似于所有表达的巨噬细胞形成蛋白的抑制。这些新的发现表明FMNL 1可能是阻碍巨噬细胞迁移的化疗靶点，这可能为限制不必要的巨噬细胞介导的炎症提供一种创新方法。我们推测，足体肌动蛋白动力学所需的formins，以支持巨噬细胞迁移。
Macrophages play a crucial role in detecting, regulating, and resolving immune crises, requiring migration through complex extracellular matrices. Unwarranted macrophage inflammatory activity potentiates kidney disease, rheumatoid arthritis, and transplant rejection. Proper remodeling of the actin cytoskeleton, especially at adhesion structures, is essential to the translocation of macrophages. Macrophages form actin-rich adhesions termed “podosomes”, giving them the capacity to make contacts with the substratum for traction through interstitial tissues. Macrophages express multiple formins, including FMNL1, Dia1, and Fhod1, with potential to impact actin remodeling involved in migration. Formins are a family of proteins that are best known for modifying the actin cytoskeleton via nucleation, elongation, bundling, and/or severing actin filaments. In this study we demonstrate that the formin FMNL1 is a key regulator of podosomes and is required for normal macrophage migration. Additionally, this is the first study to demonstrate defects in primary human cell migration resulting from specific formin silencing. Pharmacologic inhibition of all formin activity results in a significant decrease in podosome formation and normal macrophage migration. Furthermore, targeted suppression of FMNL1 results in decreases in macrophage migration similar to inhibition of all expressed macrophage formins. These novel findings suggest FMNL1 as a possible chemotherapeutic target to hinder macrophage migration, which could offer an innovative method for limiting unnecessary macrophage-mediated inflammation. We hypothesize that formins are required in podosome actin dynamics to support macrophage migration.