Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1β). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome. However, the role of inflammasome activation and pyroptosis in HBC pathophysiology remains unclear. HBCs isolated from human term placentas were treated with or without LPS or ATP, alone or in combination. Treatment of HBCs with both LPS and ATP induced the rapid secretion of high levels of IL-1β and at the same time, cell death associated with nuclear condensation and cellular swelling. HBC treatment with both LPS and ATP induced caspase-1 activation, gasdermin D (GSDMD) cleavage, which mediates pyroptosis, and IL-1β processing. Caspase-1 activation, GSDMD cleavage, IL-1β processing, and IL-1β secretion were all significantly reduced following NLRP3 knockdown; inhibition of caspase-1; and inhibition of P2X7, the receptor that mediates K⁺ efflux. Together, our data indicate that LPS and ATP treatment stimulated NLRP3 inflammasome activation and pyroptosis in HBCs leading to the rapid release of IL-1β. Since the localization of HBCs confers a unique ability to influence microbial-associated placental and fetal inflammation, these studies suggest a key role for the inflammasome and pyroptosis in mediating HBC driven inflammation.

霍夫鲍尔细胞 (HBC) 数量和蛋白质/基因表达的改变可能在微生物驱动/细胞因子介导的胎盘炎症以及随后的妊娠并发症（如绒毛炎、组织学绒毛膜羊膜炎和胎儿炎症反应综合征）中发挥作用。细胞焦亡是一种炎症形式的细胞死亡，由炎性体介导，炎性体是一种多蛋白复合物，可驱动白细胞介素 1β (IL-1β) 的加工和分泌。非胎盘巨噬细胞中的细菌脂多糖 (LPS) 和三磷酸腺苷 (ATP) 可通过激活 NLRP3 炎性体触发细胞焦亡。然而，炎性体激活和细胞焦亡在 HBC 病理生理学中的作用仍不清楚。从人类足月胎盘中分离的 HBC 用或不用 LPS 或 ATP，单独或组合处理。用 LPS 和 ATP 处理 HBC 诱导高水平 IL-1β 的快速分泌，同时，与核浓缩和细胞肿胀相关的细胞死亡。LPS 和 ATP 的 HBC 处理诱导 caspase-1 激活、gasdermin D (GSDMD) 裂解，介导细胞焦亡和 IL-1β 加工。NLRP3 敲低后，Caspase-1 激活、GSDMD 裂解、IL-1β 加工和 IL-1β 分泌均显着减少；caspase-1 的抑制；和抑制 P2X7，介导 K 的受体 NLRP3 敲低后，Caspase-1 激活、GSDMD 裂解、IL-1β 加工和 IL-1β 分泌均显着减少；caspase-1 的抑制；和抑制 P2X7，介导 K 的受体 NLRP3 敲低后，Caspase-1 激活、GSDMD 裂解、IL-1β 加工和 IL-1β 分泌均显着减少；caspase-1 的抑制；和抑制 P2X7，介导 K 的受体⁺流出。总之，我们的数据表明 LPS 和 ATP 处理刺激了 HBC 中 NLRP3 炎性体的激活和细胞焦亡，导致 IL-1β 的快速释放。由于 HBC 的定位赋予了影响微生物相关的胎盘和胎儿炎症的独特能力，这些研究表明炎性体和细胞焦亡在介导 HBC 驱动的炎症中起关键作用。