Background

Up-regulated chemerin correlates with the risk and the severity of preeclampsia. In this study, we examined impacts and underlying mechanisms by which chemerin regulates pyroptosis and trophoblast inflammation.

Methods

An in vivo preeclampsia model was established in rats and trophoblasts challenged with hypoxia/reoxygenation (H/R) with or without exogenous chemerin were used as the in vitro model. Expressions of homeobox A9 (HOXA9), chemerin, chemerin receptor (the chemokine-like receptor 1 (CMKLR1)), activated AMP-activated protein kinase (AMPK), thioredoxin-interacting protein (TXNIP), and markers related to NOD-like receptor pyrin-containing receptor 3 (NLRP3) inflammasome were examined by Western blot, and in response to AMPK inhibitor, targeting CMKLR1 or HOXA9. Cell viability and death were examined by CCK-8 and Hoechst staining, respectively. Productions of IL-1β and IL-18 in serum or culture medium were measured by ELISA. Transcriptional regulation of HOXA9 on chemerin was examined by combining expressional analysis, chromatin immunoprecipitation, and luciferase reporter assays.

Results

Up-regulations of HOXA9, chemerin, CMKLR1, TXNIP, and NLRP3 inflammasome were observed in both in vivo and in vitro models of preeclampsia, which were associated with increased death of trophoblasts and productions of IL-1β and IL-18. CMKLR1 and activated-AMPK essentially mediated chemerin effects in trophoblasts. HOXA9 directly activated the transcription of chemerin.

Conclusions

HOXA9 directly activates the transcription of chemerin, which, by activating the AMPK/TXNIP/NLRP3 inflammasome, promotes pyroptosis and inflammation of trophoblasts, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia.

中文翻译：

---

HOXA9诱导的chemerin信号通过CMKLR1/AMPK/TXNIP/NLRP3通路诱导滋养细胞焦亡并加重先兆子痫

背景

上调的凯莫瑞与先兆子痫的风险和严重程度相关。在这项研究中，我们研究了凯莫瑞调节细胞焦亡和滋养层炎症的影响和潜在机制。

方法

的体内先兆子痫模型成立于挑战与缺氧/复氧（H / R）具有或不具有外源型凯莫瑞大鼠和滋养细胞被用作体外模型。同源框 A9 (HOXA9)、chemerin、chemerin 受体（趋化因子样受体 1 (CMKLR1)）、活化的 AMP 活化蛋白激酶 (AMPK)、硫氧还蛋白相互作用蛋白 (TXNIP) 和与 NOD 样受体相关的标志物的表达通过蛋白质印迹检查含 pyrin 受体 3 (NLRP3) 炎症小体，并响应 AMPK 抑制剂，靶向 CMKLR1 或 HOXA9。分别通过 CCK-8 和 Hoechst 染色检查细胞活力和死亡。通过ELISA测量血清或培养基中IL-1β和IL-18的产生。HOXA9 对 chemerin 的转录调控通过结合表达分析、染色质免疫沉淀和荧光素酶报告基因检测来检查。

结果

在先兆子痫的体内和体外模型中均观察到 HOXA9、chemerin、CMKLR1、TXNIP 和 NLRP3 炎症小体的上调，这与滋养细胞死亡增加以及 IL-1β 和 IL-18 产生有关。CMKLR1 和激活的 AMPK 基本上介导了滋养层细胞中的凯莫瑞效应。HOXA9 直接激活凯莫瑞的转录。

结论

HOXA9 直接激活 chemerin 的转录，通过激活 AMPK/TXNIP/NLRP3 炎症小体，促进滋养细胞的焦亡和炎症，并导致先兆子痫。因此，靶向 chemerin 信号可能有益于预防和/或治疗先兆子痫。