Macrophage-associated immune checkpoint CD47 blocking ameliorates endometriosis
Macrophage-associated immune checkpoint CD47 blocking ameliorates endometriosis
复制标题
巨噬细胞相关免疫检查点 CD47 阻断可改善子宫内膜异位症
DOI：
10.1093/molehr/gaac010
复制
发表时间：
2022
影响因子：
4
通讯作者：
Guoyun Wang
中科院分区：
文献类型：
--
作者：
Jing Li;Shumin Yan;Qiuju Li;Yufei Huang;Miaomiao Ji;Xue Jiao;Ming Yuan;Guoyun Wang
抽象。腹腔巨噬细胞在子宫内膜异位症（EM）的发生发展中起重要作用，但其功能分化尚不清楚，吞噬能力较弱。CD 47信号调节蛋白α（SIRPα）和PD-L1-PD-1被认为是与巨噬细胞吞噬作用相关的免疫检查点。在大多数癌症中，这两种途径的特异性阻断已显示出增加巨噬细胞对癌细胞的吞噬清除。我们假设靶向EM中的CD 47/PD-L1可以改善巨噬细胞的吞噬作用，从而延缓EM的进展。从定位到定量，从mRNA到蛋白质，我们全面评估了EM中CD 47和PD-L1的表达。我们发现EM患者异位内膜中CD 47的表达显著增加，但PD-L1的表达没有增加。我们在体外和体内进行了子宫内膜间质细胞与巨噬细胞的直接共培养实验，以评估异位子宫内膜间质细胞是否通过CD 47-SIRPα信号通路逃避巨噬细胞的吞噬。结果表明，靶向CD 47可增加巨噬细胞的吞噬能力。有趣的是，我们还发现CD 47表达的降低促进子宫内膜间质细胞的凋亡。总之，这些数据表明，靶向CD 47可以通过增加巨噬细胞吞噬和诱导异位子宫内膜间质细胞凋亡的双重机制有效地靶向异位子宫内膜间质细胞。因此，基于CD 47-SIRPα信号通路的免疫治疗在治疗EM方面具有一定的潜力，但需要进一步的机制研究以探索更有效和特异性的抗体。
Abstract. Peritoneal macrophages play a significant role in the progression of endometriosis (EM), but their functional differentiation is still unclear, and their phagocytic ability is weak. CD47-signal-regulated protein α (SIRPα) and PD-L1-PD-1 are considered immune checkpoints associated with macrophage phagocytosis. A specific blockade of these two pathways had been shown to increase the phagocytic clearance of cancer cells by macrophages in most cancers. We hypothesized that targeting CD47/PD-L1 in EM could improve the phagocytosis of macrophages, thereby delaying the progression of EM. From localization to quantification, from mRNA to protein, we comprehensively evaluated the expression of CD47 and PD-L1 in EM. We demonstrated that the CD47 expression in ectopic endometrium from patients with EM was significantly increased, but PD-L1 was not. We performed direct co-culture experiments of endometrial stromal cells with macrophages in vitro and in vivo to assess whether ectopic endometrial stromal cells escape macrophage phagocytosis through the CD47-SIRPα signaling pathway. The results showed that targeting CD47 increased the phagocytic capacity of macrophages. Interestingly, we also found that the reduction of CD47 expression promoted apoptosis of endometrial stromal cells. In conclusion, these data suggested that targeting CD47 can effectively target ectopic endometrial stromal cells through a dual mechanism of increased phagocytosis of macrophages and induced apoptosis of ectopic endometrial stromal cells. Thus, immunotherapy based on the CD47-SIRPα signaling pathway has some potential in treating EM, but further mechanistic studies are needed to explore more effective and specific antibodies.