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

Abstract

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.