Transition of podosomes into zipper-like structures in macrophage-derived multinucleated giant cells.
Transition of podosomes into zipper-like structures in macrophage-derived multinucleated giant cells.
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DOI：
10.1091/mbc.e19-12-0707
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发表时间：
2020-08-15
影响因子：
3.3
通讯作者：
Ugarova TP
中科院分区：
文献类型：
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作者：
Balabiyev A;Podolnikova NP;Mursalimov A;Lowry D;Newbern JM;Roberson RW;Ugarova TP
巨噬细胞融合形成多核巨细胞（MGCs）是一个多阶段的过程，需要许多粘附依赖的步骤，并涉及肌动蛋白细胞骨架的重排。肌动蛋白结构的多样性及其在巨噬细胞融合中的作用尚不清楚。在这项研究中，我们揭示了迄今为止未被识别的基于肌动蛋白的拉链状结构（ZLSs），这些结构出现在植入生物材料表面形成的mgc之间。我们在小鼠巨噬细胞中建立了il -4介导融合诱导这些结构的体外模型。使用该模型，我们表明随着时间的推移，mgc发展出含有ZLSs的细胞-细胞接触。从mRFP-或eGFP-LifeAct小鼠中分离的巨噬细胞进行活细胞成像表明，ZLSs是动态的结构，经历了连续的组装和拆卸，而足质体是这些结构的前体。免疫染色实验表明，ZLSs中存在血管蛋白、talin、整合素αMβ2等足质体成分。巨噬细胞缺乏参与足小体肌动蛋白核心组织的两种关键分子WASp或Cdc42，以及用Arp2/3复合物抑制剂处理的细胞，无法形成ZLSs。此外，在相邻膜之间发现了E-cadherin和nectin-2，表明连接蛋白通过桥接质膜诱导podosomes向ZLSs转变。
Macrophage fusion resulting in the formation of multinucleated giant cells (MGCs) is a multistage process that requires many adhesion-dependent steps and involves the rearrangement of the actin cytoskeleton. The diversity of actin-based structures and their role in macrophage fusion is poorly understood. In this study, we revealed hitherto unrecognized actin-based zipper-like structures (ZLSs) that arise between MGCs formed on the surface of implanted biomaterials. We established an in vitro model for the induction of these structures in mouse macrophages undergoing IL-4–mediated fusion. Using this model, we show that over time MGCs develop cell–cell contacts containing ZLSs. Live-cell imaging using macrophages isolated from mRFP- or eGFP-LifeAct mice demonstrated that ZLSs are dynamic formations undergoing continuous assembly and disassembly and that podosomes are precursors of these structures. Immunostaining experiments showed that vinculin, talin, integrin αMβ2, and other components of podosomes are present in ZLSs. Macrophages deficient in WASp or Cdc42, two key molecules involved in actin core organization in podosomes, as well as cells treated with the inhibitors of the Arp2/3 complex, failed to form ZLSs. Furthermore, E-cadherin and nectin-2 were found between adjoining membranes, suggesting that the transition of podosomes into ZLSs is induced by bridging plasma membranes by junctional proteins.