HOXA9-induced chemerin signals through CMKLR1/AMPK/TXNIP/NLRP3 pathway to induce pyroptosis of trophoblasts and aggravate preeclampsia

Abstract 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.