Molecular Cellular and Developmental Biology Department, University of California, Santa Barbara, Santa Barbara, CA, USA.
Biomolecular Science and Engineering, University of California, Santa Barbara, Santa Barbara, CA, USA.
Dev Cell. 2024 Nov 4;59(21):2882-2896.e7. doi: 10.1016/j.devcel.2024.07.017. Epub 2024 Aug 12.
Macrophages measure the "eat-me" signal immunoglobulin G (IgG) to identify targets for phagocytosis. We tested whether prior encounters with IgG influence macrophage appetite. IgG is recognized by the Fc receptor. To temporally control Fc receptor activation, we engineered an Fc receptor that is activated by the light-induced oligomerization of Cry2, triggering phagocytosis. Using this tool, we demonstrate that subthreshold Fc receptor activation primes mouse bone-marrow-derived macrophages to be more sensitive to IgG in future encounters. Macrophages that have previously experienced subthreshold Fc receptor activation eat more IgG-bound human cancer cells. Increased phagocytosis occurs by two discrete mechanisms-a short- and long-term priming. Long-term priming requires new protein synthesis and Erk activity. Short-term priming does not require new protein synthesis and correlates with an increase in Fc receptor mobility. Our work demonstrates that IgG primes macrophages for increased phagocytosis, suggesting that therapeutic antibodies may become more effective after initial priming doses.
巨噬细胞通过测量“吃我”信号免疫球蛋白 G（IgG）来识别吞噬作用的目标。我们测试了之前是否遇到过 IgG 是否会影响巨噬细胞的食欲。IgG 被 Fc 受体识别。为了暂时控制 Fc 受体的激活，我们设计了一种 Fc 受体，它可以通过 Cry2 的光诱导寡聚化激活，从而触发吞噬作用。使用该工具，我们证明亚阈值 Fc 受体激活可使小鼠骨髓来源的巨噬细胞在未来的接触中对 IgG 更敏感。先前经历过亚阈值 Fc 受体激活的巨噬细胞会吃掉更多结合 IgG 的人类癌细胞。两种不同的机制——短期和长期的启动——可增加吞噬作用。长期启动需要新的蛋白质合成和 Erk 活性。短期启动不需要新的蛋白质合成，并且与 Fc 受体的流动性增加相关。我们的工作表明 IgG 可使巨噬细胞对吞噬作用的敏感性增强，这表明治疗性抗体在初始启动剂量后可能会更有效。
