Mice decidua and placenta (PRJCA016274)
Interferon-stimulating genes (ISGs) activated by proper interferon signal play an important role in promoting successful pregnancy, but the high level of interferon-I response induced in the autoimmune pregnancy or virus infection is also associated with adverse pregnancy outcomes (APOs). Identification of pathogenic ISGs provides the possibility for accurate treatment of pregnancy-related diseases. Here, we found that RSAD2 (radical S-adenosyl methionine domain containing 2) is a pathogenic ISG, and it up-regulated expression causes a large amount of lipids to accumulate in the placenta and destroy angiogenesis, leading to embryonic development disorders. RSAD2 was highlighted in screening ISGs that is abnormally active in the maternal and fetal microenvironment of systemic lupus erythematosus (SLE) patients based on the ISGs qPCR array. In mechanism, we found RSAD2 promotes lipid metabolism disorder, causing DAG-lipids accumulation and seriously suppressing vasculogenesis signaling pathway in placenta. In the mouse pregnancy model stimulated by IFN-I inducer poly (I: C), the phenotype of lipid excess accumulation, vascular injury and embryo development disorder was significantly relieved in the Rsad2-deficient mouse pregnancy model. We tested spontaneous SLE mouse pregnancy models and SLE patients, which have APOs, and found that the expression of this pathogenic RSAD2 at the maternal-fetal interface was significantly increased, accompanied by Lipid metabolism disorders at the maternal-fetal interface. Our work reveals the molecular mechanism of RSAD2 leading to adverse pregnancy outcomes, and provides new targets for clinical treatment of pregnancy patients with high interferon response.