RLR pathways in pregnancy: Guardians of antiviral immunity and mediators of inflammation-driven complications

Abstract

Pregnancy demands dynamic immune adaptations to support implantation, fetal growth, and labor while maintaining maternal-fetal tolerance. The immune profile shifts from pro-inflammatory during implantation to anti-inflammatory in mid-pregnancy, reverting to inflammation at labor onset. Key immune cells like NK cells, macrophages, dendritic cells, and T cells dominate the decidua, guiding successful placental development. These immune cells express pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), Nod-like receptors (NLRs), and C-type lectin receptors (CLRs) at the maternal–fetal interface and detect pathogen-associated molecular patterns (PAMPs) during pathological conditions. Among them, RIG-I-like receptors (RLRs), including RIG-I and MDA5, are expressed in syncytiotrophoblasts and cytotrophoblasts, where they sense RNA viruses like Zika and dengue during pregnancy. RLR signalling in pregnancy is modulated by hormones like estrogen and glucocorticoids. Cellular metabolic product lactate also regulates this signalling. The RLR signaling pathway is crucial for antiviral defense at the maternal-fetal interface, but its dysregulation can lead to complications like preeclampsia and preterm birth. Therapeutic targeting of RLR components and interferon regulators offers promising treatment avenues. Diagnostic biomarkers like circulating RLR molecules may aid in early detection of pregnancy disorders. Overall, RLR signaling presents both therapeutic and diagnostic potential in managing inflammation-associated pregnancy complications.