Chemokines help coordinate inflammation within the fetal‐maternal microenvironment during gestation. The chemokine CXCL12 signaling through its receptor CXCR4 regulates inflammatory activity, but this phenomenon is not well understood during pregnancy, and there are no reports exploring the role of this pair in peripheral immune tolerance during gestation. Herein, we hypothesize that intrauterine CXCL12‐CXCR4 signaling governs local and systemic immunomodulatory dynamics during early gestation in ewes.

Osmotic pumps were surgically installed for intrauterine infusion of a CXCR4 inhibitor, AMD3100, beginning on day 12 post‐breeding in sheep. Endometrial tissues were collected on day 35 of gestation and evaluated for inflammatory potential, Akt pathway activation, and autophagy induction. Demonstrative of peripheral immune activity, levels of select cytokines were assessed in daily blood samples collected throughout the study, as well as in corpus luteum and spleen on day 35.

Anti‐inflammatory IL10 was primarily localized to endometrial glandular epithelium with lower abundance when CXCR4 was antagonized. Inhibition of CXCR4 at the fetal‐maternal interface resulted in less activation of Akt in endometrium, while evidence of autophagy induction was greater. Corpora lutea from ewes receiving intrauterine AMD3100 exhibited lower interferon‐gamma (IFNG) expression. Blood inflammatory potential was differentially altered in a temporal fashion throughout infusion. IL10 abundance in spleen was greater following CXCR4 inhibition at the fetal‐maternal interface, while IFNG was less.

Intrauterine CXCL12‐CXCR4 signaling governs endometrial and systemic inflammation; disruption of this axis may have detrimental impacts on offspring and maternal health.