RESUMO
A higher ratio of M1/M2 macrophages and an elevated chemerin level are both related to increased risk of preeclampsia. However, the crosstalk between these two events and their collective contribution to preeclampsia are not well understood. In this study, we assessed the impacts of chemerin chemokine-like receptor 1 (CMKLR1)/p-Akt/CEBPα axis in regulating macrophage polarization and mediating the pathogenic effects of chemerin on preeclampsia. We showed that chemerin, in a dose- and time-dependent manner, stimulated M1 macrophage polarization, inhibited macrophage-induced trophoblast invasion and migration, and suppressed macrophage-mediated angiogenesis. All these chemerin-induced phenotypes are essentially mediated by sequentially CMKLR1, Akt activation, and CEBPα. Mechanistically, CEBPα acted as a transcriptional activator for both IRF8 and chemerin. In vivo, chemerin aggravated preeclampsia, while α-NETA, an inhibitor for CMKLR1, significantly suppressed M1 macrophage polarization and alleviated preeclampsia. In summary, chemerin, by activating CMKLR1/Akt/CEBPα axis, forms a positive feedback loop, promotes M1 macrophage polarization, suppresses trophoblast migration/invasion and angiogenesis, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia.
Assuntos
Quimiocinas , Pré-Eclâmpsia , Receptores de Quimiocinas , Animais , Quimiocinas/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/patologia , Pré-Eclâmpsia/patologia , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
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-1ß 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-1ß 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.
Assuntos
Quimiocinas/genética , Inflamação/genética , Pré-Eclâmpsia/genética , Piroptose/genética , Quinases Proteína-Quinases Ativadas por AMP/genética , Animais , Proteínas de Ciclo Celular/genética , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Proteínas de Homeodomínio , Inflamação/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Receptores de Quimiocinas/genética , Transdução de Sinais/genética , Trofoblastos/metabolismo , Trofoblastos/patologiaRESUMO
Myocyte enhancer factor 2C (MEF2C) is a transcription factor of MADS box family involved in the early development of several human cells including muscle (i.e., skeletal, cardiac, and smooth), neural, chondroid, immune, and endothelial cells. Dysfunction of MEF2C leads to embryo hypoplasia, disorganized myofibers and perinatal lethality. The main role of MEF2C is its regulation of muscle development. It has been reported that MEF2C-knockout mice die on embryonic day 9.5 from unnatural development of cardiovascular. The effects of MEF2C are mediated by its directly-interacting proteins; therefore, the investigation of these interactions is critical in order to clarify MEF2C's biological function. In this study, we review twenty-five proteins that directly interact with MEF2C, including nineteen proteins related to muscle development, four proteins related to neural cell development, one protein related to chondroid cell development, four proteins related to immune cell development, and two proteins related to endothelial cell development. Among these proteins, the interaction of MEF2C with MRFs is important for differentiation of developing muscle cells. MEF2C interacts with Sox18 for endothelial vessel morphogenesis. The interaction of MEF2C with Cabin1 is important for maintaining T-cell inactivation. Investigating the interactions of MEF2C and its directly-interacting proteins is not only helpful to understand of the physiological function of MEF2C, but also provides a target for future rational drug design.
