Maternal CXCR4 deletion results in placental defects and pregnancy loss mediated by immune dysregulation

Abstract

CXCR4 is a key regulator of the development of NK cells and DCs, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. Our study demonstrates that adult-induced global genetic CXCR4 deletion, but not uterine-specific CXCR4 deletion, was associated with increased pregnancy resorptions and decreased litter size. CXCR4-deficient mice had decreased NK cells and increased granulocytes in the decidua, along with increased leukocyte numbers in peripheral blood. We found that CXCR4-deficient mice had abnormal decidual NK cell aggregates and NK cell infiltration into trophoblast areas beyond the giant cell layer. This was associated with low NK cell expression of granzyme B, a NK cell granule effector, indicative of NK cell dysfunction. Pregnancy failure in these mice was associated with abnormalities in placental vascular development and increased placental expression of inflammatory genes. Importantly, adoptive BM transfer of WT CXCR4 + BM cells into CXCR4-deficient mice rescued the reproductive deficits by normalizing NK cell function and mediating normal placental vascular development. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development, and pregnancy maintenance.

Autophagy Inhibition in Trophoblasts Induces Aberrant Shift in CXCR4+ Decidual NK Cell Phenotype Leading to Pregnancy Loss

“…In murine models lacking CXCR4, a decrease in dNK cell numbers is observed, coupled with abnormal formation of abnormal dNK cell aggregates and the infiltration of NK cells into trophoblast areas beyond the giant cell layer. Additionally, these changes are concomitant with diminished NK cell expression of granzyme B, a crucial effector molecule indicative of impaired NK cell function [11]. Importantly, a reduced proportion of CXCR4 + NK cells is not only documented in patients with recurrent implantation failure [12] but also in those experiencing RSAs [7].…”