Homeostatic macrophages prevent preterm birth and improve neonatal outcomes by mitigatingin uterosterile inflammation

Abstract

Preterm birth (PTB), commonly preceded by preterm labor, is the leading cause of neonatal morbidity and mortality worldwide. Recent advances in next-generation sequencing have revealed that most cases of preterm labor are associated with sterile intra-amniotic inflammation (SIAI), an inflammatory condition without detectable microorganisms. To date, no successful strategies to treat SIAI have been developed. Herein, we present mechanistic proof that treatment with M2-polarized macrophages (M2 Mϕ) can effectively prevent SIAI-induced PTB and neonatal mortality. M2 Mϕ halt the premature pathway of labor by infiltrating maternal and fetal compartments, where they inhibit NLRP3 inflammasome activation triggered by HMGB1. Furthermore, M2 Mϕ dampen the HMGB1-induced inflammatory response in the amniotic cavity and fetal lung. Notably, neonates exposed to HMGB1in uterodisplay a reduced capacity to clear bacterial infection and gut microbiome dysbiosis, which are restored by M2 Mϕ treatment. Our findings provide cogent evidence that M2 Mϕ can serve as a cellular strategy to mitigate PTB and decrease neonatal mortality.