M2-polarized macrophages as a potential cell therapy to mitigate inflammation-induced preterm birth

Abstract

Abstract Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. A substantial fraction of spontaneous preterm births are due to intra-amniotic inflammation; yet, to date, no anti-inflammatory strategies exist to treat this clinical condition. We propose that boosting homeostatic immune cells that are reduced at the maternal-fetal interface of women who underwent preterm birth can serve as a novel strategy to prevent this syndrome. First, using immunophenotyping, we showed that women who experience preterm birth have low proportions of M2-polarized macrophages at the maternal-fetal interface. Next, we tested whether adoptive transfer of M2-polarized macrophages could prevent intra-amniotic inflammation-induced preterm birth in mice. Bone marrow-derived myeloid cells (BMDM) from non-pregnant mice were differentiated and polarized towards M2 macrophages, as proven by flow cytometry. The adoptive transfer of M2-polarized macrophages, but not BMDM, prevented preterm birth and neonatal death. To increase the translational value, M2-polarized macrophages from mid and late pregnancy were also tested, and those from mid pregnancy were more effective in preventing preterm birth. Using GFP-positive M2-polarized macrophages, we showed that adoptively transferred cells migrate into the maternal (lung, liver, uterus) and fetal (placenta, lung) tissues as well as the maternal-fetal interface prior to preterm birth. The adoptive transfer of M2-polarized macrophages dampened pro-inflammatory responses in the maternal circulation and amniotic cavity. Collectively, these findings raise the prospect of a novel cellular anti-inflammatory approach to prevent preterm birth and adverse neonatal outcomes.