RSAD2: A pathogenic interferon-stimulated gene at the maternal-fetal interface of patients with systemic lupus erythematosus
Xiaoyu Ding, Yonggang Zhou, Yonggang Zhou, Xiaofeng Qiu, Xiuxiu Xu, Xinyu Hu, Jingkun Qin, Yulan Chen, Min Zhang, Jieqi Ke, Zhenbang Liu, Ying Zhou, Ying Zhou, Chen Ding, Nan Shen, Zhigang Tian, Binqing Fu, Haiming Wei
Abstract
Pregnancy disorders in patients with autoimmune diseases or viral infections are often associated with an excessive response of type I interferons. We identify radical S-adenosyl methionine domain containing 2 (RSAD2) as a pathogenic interferon-stimulated gene (ISG) associated with pregnancy complications in systemic lupus erythematosus (SLE). The increased expression of RSAD2 mainly occurs in macrophages and structural cell populations at the maternal-fetal interface of pregnant patients with SLE. The elevation of RSAD2 leads to the accumulation of diacylglycerol lipids in the placenta, impairing the necessary vascular development for the fetus. Depletion of Rsad2 in pregnant mice models exposed to type I interferon inducers significantly reduces lipid accumulation, vascular injury, and embryo development disorders. An RSAD2 inhibitor, L-chicoric acid (LCA), alleviates lipid accumulation and vascular damage, improving pregnancy outcomes in SLE-induced and spontaneous mouse models. This study proposes the potential of targeting RSAD2 to improve pregnancy outcomes in individuals with heightened type I interferon response. • RSAD2 as a pathogenic interferon-stimulated gene at the maternal-fetal interface • RSAD2 excess increases lipid load in structural cell populations • RSAD2-induced lipid accumulation impairs placental vasculogenesis • LCA targeting of RSAD2 alleviates lipid-induced vascular inflammation The role of type I interferon response at the maternal-fetal interface is complex. Ding et al. identify RSAD2 as a pathogenic ISG in SLE pregnancies, where it drives placental lipid accumulation and impairs vasculogenesis, with LCA targeting RSAD2 to improve pregnancy outcomes.