# Dipeptidylpeptidase 4 inhibition attenuates gestational pathologies via immune homeostasis restoration in the pulmonary-uterine axis

## TL;DR

This study shows that DPP4 inhibitors can reduce pregnancy complications by restoring immune balance in the lungs and uterus after viral infections.

## Contribution

The paper identifies a lung-uterus immune axis and proposes DPP4 inhibition as a novel therapeutic strategy for viral-induced pregnancy issues.

## Key findings

- Respiratory viral infections impair uterine immune activation and embryonic growth.
- DPP4 inhibition with sitagliptin restores immune homeostasis in both the lung and uterus.
- IL1R2⁺ myeloid cells migrate from the lung to the decidua, disrupting gestational immunity.

## Abstract

Respiratory viral infections during pregnancy threaten maternal pulmonary health and fetal development, however the mechanisms linking lung infection to distant uterine immune disruption remain unclear. Here, we demonstrate that respiratory viral infection attenuates uterine immune activation, impairing vascular remodeling and trophoblast invasion, which compromises embryonic growth. Treatment with the dipeptidylpeptidase 4 (DPP4) inhibitor sitagliptin restores immune homeostasis in both the lung and uterus, markedly reducing pregnancy complications. Mechanistically, while pulmonary infection expands interleukin-1 receptor type 2–expressing (IL1R2⁺) CD11b⁺ myeloid cells in the lung, this expansion is attenuated by DPP4 inhibition. These cells migrate to the decidua and disrupt pregnancy-maintaining immune signaling. Single-cell RNA sequencing confirms accumulation of IL1R2⁺ regulatory macrophages at both sites. Genetic Il1r2 ablation similarly reduces uterine IL1R2⁺ cells and restores gestation. This study reveals a lung-uterus immune axis and identifies DPP4 inhibition as a dual-organ therapeutic strategy against viral-induced pregnancy pathology.

The mechanism of respiratory viral infection impacting distant immune responses in the uterus remains to be explored. The authors here identify pulmonary infection induces IL1R2⁺ myeloid cells migration to decidua, disrupting gestational immunity. Dipeptidyl peptidase 4 (DPP4) inhibitor treatment curbs this cell accumulation and alleviates immune dysregulation.