M2 macrophages dampen in utero sterile inflammation to prevent preterm birth and improve neonatal outcomes

Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Recent advancements in next-generation sequencing have revealed that most cases of preterm labor are associated with intra-amniotic inflammation without detectable microorganisms, a condition termed sterile intra-amniotic inflammation (SIAI). Currently, there are no established strategies to effectively treat SIAI. In this study, using an animal model of SIAI, we present mechanistic evidence demonstrating that treatment with M2 macrophages can effectively prevent PTB and mitigate adverse neonatal outcomes. We show that M2 macrophages disrupt the premature pathway of labor by suppressing inflammatory responses, including inflammasome activation, in the amniotic cavity (amniotic fluid and fetal membranes), as well as placental, fetal, and neonatal lung inflammation. Importantly, neonates exposed to SIAI exhibit compromised gut inflammation and stereotypical microbiome dysbiosis, both of which are restored by treatment with M2 macrophages. Furthermore, the long-lasting effects of M2 macrophage treatment enhance neonatal resistance to Group B Streptococcus infection. Collectively, our findings provide compelling evidence that M2 macrophages can serve as a cellular strategy to mitigate PTB and improve neonatal outcomes induced by in utero sterile inflammation. ### Competing Interest Statement The authors have declared no competing interest.