SIRT1-NCOR2 Corepressor Modulates Trophoblast-Macrophage Interactions in Preeclampsia

Preeclampsia is a severe hypertensive disorder of pregnancy associated with low SIRT1 (sirtuin 1) levels in trophoblasts. Single-cell sequencing showed abnormal activation of trophoblast Rarres2 (retinoic acid receptor responder 2) and macrophage Cmklr1 (chemokine-like receptor 1) at the maternal-fetal interface in systemic Sirt1 heterozygous knockout mice. This study investigated how low SIRT1 in trophoblasts increases RARRES2 expression, affecting macrophage polarization and preeclampsia pathogenesis.

We conducted coculture experiments to analyze trophoblast RARRES2 and macrophage CMKLR1 interactions, performed luciferase and chromatin immunoprecipitation assays to validate transcription factors for RARRES2 in trophoblasts, and utilized mass spectrometry and immunoprecipitation to identify transcriptional coregulators. cKO (trophoblast-specific Sirt1 knockout) mice were generated and treated with Rarres2 knockout or progesterone supplementation to validate the role of the SIRT1/RARRES2 axis in preeclampsia pathogenesis and prevention by progesterone. Finally, we measured RARRES2 and SIRT1 levels in the plasma of patients with preeclampsia.

Low-SIRT1 expression in trophoblasts promoted M1-type macrophage polarization and inhibited trophoblast invasion, mediated by the RARRES2-CMKLR1 interaction. SIRT1 regulated RARRES2 expression in trophoblasts by recruiting NCOR2 (nuclear receptor corepressor 2). cKO mice showed preeclampsia-like symptoms and RARRES2-CMKLR1 activation at the maternal-fetal interface, which were reversed by Rarres2 knockout or progesterone supplementation. Notably, RARRES2 levels were higher and were a risk factor, whereas SIRT1 levels were lower and were a protective factor for preeclampsia in early pregnancy.

This study highlights SIRT1's potential role in regulating abnormal trophoblast-macrophage interactions at the maternal-fetal interface in preeclampsia and offers a new strategy for its early prediction and prevention.