Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation.
Mechanotransduction via a TRPV4-Rac1 signaling axis plays a role in multinucleated giant cell formation.
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DOI：
10.1074/jbc.ra120.014597
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Rahaman SO
中科院分区：
文献类型：
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作者：
Arya RK;Goswami R;Rahaman SO
多核巨细胞是由巨噬细胞融合形成的，是包括异物反应（FBR）在内的许多病理生理状况的特征。异物巨细胞（FBGC）是炎症性和破坏性多核巨噬细胞，可能导致植入物损伤和/或排斥。然而，虽然FBGCs的这些特征已经很好地建立，但其形成的分子机制仍然难以捉摸。对FBGCs形成的分子机制的进一步理解可能会允许开发消除或减少FBR的新型植入物。我们以前的研究表明，瞬时受体电位香草酸4（TRPV 4），一个机械敏感的离子通道/受体，是FBGC形成和生物材料的FBR所必需的。在这里，我们已经确定（a）TRPV 4直接参与融合细胞因子，（B）TRPV 4与Rac 1直接相互作用，并且它们的相互作用在融合细胞因子存在下进一步增强;（c）Rac 1的TRPV 4依赖性激活对于细胞内硬度的增加和细胞骨架重塑的调节是必不可少的;和（d）TRPV 4-Rac 1信号传导轴在促融合的精氨酸诱导的FBGC形成中是关键的。总之，这些数据表明了一种新的机制，即TRPV 4和Rac 1之间的功能相互作用导致细胞骨架重塑和细胞内刚度的产生，以调节FBGC的形成。
Multinucleated giant cells are formed by the fusion of macrophages and are a characteristic feature in numerous pathophysiological conditions including the foreign body response (FBR). Foreign body giant cells (FBGCs) are inflammatory and destructive multinucleated macrophages and may cause damage and/or rejection of implants. However, while these features of FBGCs are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGCs may permit the development of novel implants that eliminate or reduce the FBR. Our previous study showed that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel/receptor, is required for FBGC formation and FBR to biomaterials. Here, we have determined that (a) TRPV4 is directly involved in fusogenic cytokine (interleukin-4 plus granulocyte macrophage–colony stimulating factor)–induced activation of Rac1, in bone marrow–derived macrophages; (b) TRPV4 directly interacts with Rac1, and their interaction is further augmented in the presence of fusogenic cytokines; (c) TRPV4-dependent activation of Rac1 is essential for the augmentation of intracellular stiffness and regulation of cytoskeletal remodeling; and (d) TRPV4-Rac1 signaling axis is critical in fusogenic cytokine–induced FBGC formation. Together, these data suggest a novel mechanism whereby a functional interaction between TRPV4 and Rac1 leads to cytoskeletal remodeling and intracellular stiffness generation to modulate FBGC formation.