Preeclampsia (PE) is a serious complication, and soluble fms-like tyrosine kinase (sFLT1) released from the placenta is one of the causes of PE pathology. Trophoblasts are the primary source of sFLT1; however, monocytes/macrophages exist enough in the placenta can also secrete sFLT1. Sterile inflammatory responses, especially NLRP3 inflammasome and its downstream gasdermin D (GSDMD)-regulated pyroptosis, may be involved in the development of PE pathology. In this study, we investigated whether human monocyte/macrophage cell line THP-1 cells secrete sFLT1 depending on the NLRP3 inflammasome and GSDMD. To differentiate THP-1 monocytes into macrophages, treatment with phorbol 12-myristate 13-acetate (PMA) induced sFLT1 with interleukin (IL)− 1β, but did not induce cell lytic death. IL-1β secretion induced by PMA inhibited by deletion of NLRP3 and inhibitors of NLRP3 and caspase-1, but deletion of NLRP3 and these inhibitors did not affect sFLT1 secretion in THP-1 cells. Both gene deletion and inhibition of GSDMD dramatically decreased IL-1β and sFLT1 secretion from THP-1 cells. Treatment with CA074-ME (a cathepsin B inhibitor) also reduced the secretion of both sFLT1 and IL-1β in THP-1 cells. In conclusion, THP-1 macrophages release sFLT1 in a GSDMD-dependent manner, but not in the NLRP3 inflammasome-dependent manner, and this sFLT1 release may be associated with the non-lytic role of GSDMD. In addition, sFLT1 levels induced by PMA are associated with lysosomal cathepsin B in THP-1 macrophages. We suggest that sFLT1 synthesis regulated by GSDMD are involved in the pathology of PE.

中文翻译：

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Gasdermin D 调节巨噬细胞中可溶性 fms 样酪氨酸激酶 1 的释放

先兆子痫（PE）是一种严重的并发症，胎盘释放的可溶性fms样酪氨酸激酶（sFLT1）是PE病理的原因之一。滋养层细胞是 sFLT1 的主要来源；然而，胎盘中存在足够多的单核细胞/巨噬细胞也可以分泌sFLT1。无菌炎症反应，特别是NLRP3炎症小体及其下游gasdermin D (GSDMD)调节的细胞焦亡，可能参与PE病理学的发展。在本研究中，我们研究了人单核/巨噬细胞系 THP-1 细胞是否根据 NLRP3 炎症小体和 GSDMD 分泌 sFLT1。为了将 THP-1 单核细胞分化为巨噬细胞，用佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 处理可诱导白细胞介素 (IL)−1β 的 sFLT1，但不会诱导细胞裂解性死亡。 NLRP3以及NLRP3和caspase-1抑制剂的缺失抑制了PMA诱导的IL-1β分泌，但NLRP3和这些抑制剂的缺失并不影响THP-1细胞中sFLT1的分泌。基因删除和 GSDMD 抑制均显着降低了 THP-1 细胞的 IL-1β 和 sFLT1 分泌。 CA074-ME（一种组织蛋白酶 B 抑制剂）治疗也减少了 THP-1 细胞中 sFLT1 和 IL-1β 的分泌。总之，THP-1巨噬细胞以GSDMD依赖性方式释放sFLT1，而不是以NLRP3炎性体依赖性方式释放sFLT1，并且这种sFLT1释放可能与GSDMD的非裂解作用有关。此外，PMA 诱导的 sFLT1 水平与 THP-1 巨噬细胞中的溶酶体组织蛋白酶 B 相关。我们认为 GSDMD 调节的 sFLT1 合成参与了 PE 的病理学。