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 (FBGC) are inflammatory and destructive multinucleated macrophages, and may cause damage and/or rejection of implants. However, while these features of FBGC are well established, the molecular mechanisms underlying their formation remain elusive. Improved understanding of the molecular mechanisms underlying the formation of FBGC 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.

中文翻译：

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通过 TRPV4-Rac1 信号轴的机械转导在多核巨细胞形成中发挥作用

多核巨细胞由巨噬细胞融合形成，是包括异物反应（FBR）在内的多种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，可能会导致植入物损坏和/或排斥。然而，虽然 FBGC 的这些特征已得到充分证实，但其形成背后的分子机制仍然难以捉摸。对 FBGC 形成分子机制的进一步了解可能有助于开发消除或减少 FBR 的新型植入物。我们之前的研究表明，瞬态受体电位香草酸 4 (TRPV4)（一种机械敏感离子通道/受体）是 FBGC 形成和生物材料 FBR 所必需的。在此，我们确定：(a) TRPV4 直接参与骨髓源性巨噬细胞中融合细胞因子（白细胞介素 4 加粒细胞巨噬细胞集落刺激因子）诱导的 Rac1 激活；(b) TRPV4 直接与 Rac1 相互作用，并且它们的相互作用在融合细胞因子的存在下进一步增强；(c) TRPV4 依赖性 Rac1 激活对于增强细胞内硬度和调节细胞骨架重塑至关重要；(d) TRPV4-Rac1 信号轴在融合细胞因子诱导的 FBGC 形成中至关重要。总之，这些数据表明了一种新机制，TRPV4 和 Rac1 之间的功能相互作用导致细胞骨架重塑和细胞内刚度产生，从而调节 FBGC 形成。