Amsterdam UMC location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, University of Amsterdam, The Netherlands; Amsterdam Institute for Immunology and Infectious diseases, University of Amsterdam, The Netherlands.
Medical Systems Biophysics and Bioengineering, Leiden Academic Centre for Drug Research, Faculty of Mathematics and Natural Sciences, Leiden University, Leiden, The Netherlands.
Eur J Cell Biol. 2024 Jun;103(2):151419. doi: 10.1016/j.ejcb.2024.151419. Epub 2024 May 15.
Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While cellular mechanics have been implicated in inflammation, the contribution of Nur77 to these mechanical processes remains elusive. Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. To establish the potential correlation of Nur77 with cellular mechanics, we compared bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Nur77-deficient (Nur77-KO) mice and employed cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis assays, and RNA-sequencing. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent in vitro experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics. Our findings suggest that immune regulation by Nur77 may be partially mediated through alterations in cellular mechanics, highlighting a potential avenue for therapeutic targeting.
核受体 Nur77 在各种组织的免疫调节中发挥关键作用，影响促炎信号通路和细胞代谢。虽然细胞力学已被牵涉到炎症中，但 Nur77 对这些力学过程的贡献仍不清楚。巨噬细胞在形态和力学上表现出显著的可塑性，使它们能够适应和执行重要的炎症功能，如在炎症组织中导航和吞噬病原体。然而，在炎症过程中调节巨噬细胞力学这些动态变化的确切调控机制仍知之甚少。为了确定 Nur77 与细胞力学之间的潜在相关性，我们比较了野生型（WT）和 Nur77 缺失型（Nur77-KO）小鼠的骨髓来源巨噬细胞（BMDM），并采用细胞骨架成像、单细胞声学力谱（AFS）、迁移和吞噬测定以及 RNA 测序。我们的研究结果表明，与 WT BMDM 相比，Nur77-KO BMDM 的肌动蛋白网络发生变化，这与更硬和更刚性的表型相关。随后的体外实验验证了我们的观察结果，表明 Nur77 缺失导致迁移增强、黏附减少和吞噬活性增加。转录组学数据证实了 Nur77 缺陷型巨噬细胞中与力学相关的途径发生改变，同时伴有强烈的促炎表型。利用之前获得的 ChIP 数据，我们揭示 Nur77 直接靶向与细胞力学相关的差异表达基因。总之，虽然 Nur77 通过抑制促炎基因的表达来减少巨噬细胞的炎症，但我们的研究确定了一种新的调控机制，即 Nur77 通过调节参与细胞力学的基因的表达来调节巨噬细胞炎症。我们的研究结果表明，Nur77 的免疫调节可能部分通过改变细胞力学来介导，这突出了一个潜在的治疗靶点。
