A conserved EREG+IL1RN+ macrophage program defines an inflammation-associated transcriptional state linked to WTAP reprogramming and preterm premature rupture of membranes

Preterm premature rupture of membranes (PPROM) is a major cause of spontaneous preterm birth, yet the cellular mechanisms linking inflammation to membrane dysfunction remain incompletely understood. Here, we integrated single-cell and single-nucleus transcriptomic datasets from multiple maternal-fetal interface tissues to construct a comprehensive atlas of inflammatory signaling during early pregnancy. Macrophages emerged as the predominant source of basal inflammatory activity, and secondary clustering identified a conserved EREG + IL1RN + macrophages characterized by elevated inflammatory and innate immune programs. Pseudotime analysis revealed a transcriptional progression from proliferative and immunoregulatory macrophage states toward inflammatory and immune-effector states, with EREG + IL1RN + macrophages exhibiting a distinct transcriptional profile. Independent single-nucleus and spatial transcriptomic datasets confirmed the transcriptional and spatial conservation of this population. In placental infection datasets, EREG + IL1RN + macrophages were markedly expanded and enriched for cytokine signaling, leukocyte recruitment, and extracellular matrix remodeling pathways. WTAP , an m 6 A-associated candidate regulator, was positively associated with inflammatory macrophage programs, and its depletion attenuated inflammatory gene expression while promoting immunity hub-associated signatures. Clinically, the EREG + IL1RN + macrophage signature was significantly enriched in PPROM fetal membranes and showed the strongest ability to distinguish PPROM from preterm labor controls. Together, these findings identify EREG + IL1RN + macrophages as a conserved inflammatory macrophage program and implicate WTAP in inflammatory macrophage remodeling at the maternal-fetal interface.