ADAR1 as a Placental Innate Immune Rheostat Sustaining the Homeostatic Balance of Intrinsic Interferon Response at the Maternal-Fetal Interface.

The mechanisms that balance a robust intrinsic antiviral defense at the maternal-fetal interface with fetal development remain elusive. Here, it is delineated that ADAR1, an adenosine-to-inosine (A-to-I) editor, fine-tunes intrinsic interferon (IFN)-mediated integrates stress response (ISR) in the mouse placenta, thereby orchestrating embryonic development and antiviral defense. Placental Adar1 deletion (Adar1(PKO)) trigger spatially resolved overwhelming IFN responses, which impair the differentiation of IFN hyper-responsive junctional zone (JZ) progenitors and functions of the placental JZ, ultimately causing embryonic death. Mechanistically, the Adar1(PKO) placental IFN hyper-response is positively amplified by the accumulated immunogenic dsRNAs from the 3'UTR of interferon-stimulated genes (ISG-3'UTR-dsRNA). The resulting fetal death is rescued by concurrent deletion of Mavs, Ifnar1, or Pkr, but not Zbp1 or cell death effectors. Notably, blocking ISR pharmacologically preventes embryonic lethality induced by Adar1(PKO) JZ defects. These findings demonstrate that ADAR1 fine-tunes the unique spatially resolved IFN-PKR-ISR signaling in the placenta by restricting ISG-3'UTR-dsRNA accumulation, highlighting a potential therapeutic strategy for treating interferonopathy-associated pregnancy complications.