Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA.
Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA, USA.
Sci Adv. 2020 Dec 4;6(49). doi: 10.1126/sciadv.abb8471. Print 2020 Dec.
Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.
巨噬细胞是先天免疫细胞，它们附着在组织内的细胞外基质上。然而，基质特性如何调节其功能仍知之甚少。在这里，我们报告说，黏附的微环境通过转录共激活因子 YAP 来调节巨噬细胞的炎症反应。我们发现，与在硬材料上黏附相比，黏附在柔软的水凝胶上可减少炎症，并且与 YAP 表达和核定位减少相关。基质硬度和细胞骨架聚合，而不是黏附限制或收缩性，调节 YAP 的定位。此外，YAP 的耗竭可抑制巨噬细胞炎症，而过表达活性 YAP 则会增加炎症。最后，我们体内实验显示，与硬材料相比，软材料可降低周围巨噬细胞中炎症标志物和 YAP 的表达。总之，我们的研究确定了 YAP 是控制巨噬细胞炎症和感知其硬度的关键分子，这可能对健康和疾病中巨噬细胞的调节具有广泛的意义。
