A conserved EREG+IL1RN+ macrophage program defines an inflammation-associated transcriptional state linked to WTAP reprogramming and preterm premature rupture of membranes
- 1epartment of Obstetrics and Gynecology, Binhai County People’s Hospital, Yancheng, Jiangsu, China
Abstract
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 m6A-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.
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BibTeX
@article{zheng2026conserved,
title = {{A conserved EREG+IL1RN+ macrophage program defines an inflammation-associated transcriptional state linked to WTAP reprogramming and preterm premature rupture of membranes}},
author = {Meng Zheng and Qiulan Yu and Xiaowei Zhang and Ping Yuan and Tongtong Liu and Haihong Wang},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1903568},
url = {https://doi.org/10.3389/fcell.2026.1903568},
note = {CC BY},
}
RIS
TY - JOUR
TI - A conserved EREG+IL1RN+ macrophage program defines an inflammation-associated transcriptional state linked to WTAP reprogramming and preterm premature rupture of membranes
AU - Meng Zheng
AU - Qiulan Yu
AU - Xiaowei Zhang
AU - Ping Yuan
AU - Tongtong Liu
AU - Haihong Wang
PY - 2026
DA - 2026/10/28
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1903568
UR - https://doi.org/10.3389/fcell.2026.1903568
AB - 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 m6A-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.
SN - 2296-634X
ER -