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

## TL;DR

ADAR1 helps balance immune responses in the placenta to protect both the fetus and the mother during pregnancy.

## Contribution

ADAR1 is shown to regulate placental interferon responses by controlling dsRNA accumulation from interferon-stimulated genes.

## Key findings

- Placental Adar1 deletion causes excessive IFN responses and embryonic death.
- ISR inhibition rescues embryonic lethality caused by Adar1PKO JZ defects.
- ISG-3′UTR-dsRNA accumulation drives placental IFN hyper-response in Adar1PKO.

## Abstract

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 (Adar1PKO
) 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 Adar1PKO
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 Adar1PKO
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.

This study reveals that ADAR1, an RNA‐editing enzyme, fine‐tunes immune responses in the placenta by preventing the accumulation of immunogenic double‐stranded RNAs (dsRNAs) from interferon‐stimulated genes. The loss of ADAR1 in the placenta leads to excessive interferon signaling restricted to the junctional zone, disrupting placental development and causing embryonic death, which is rescued by blocking interferon‐induced integrated stress response (ISR).