Immune Mechanisms That Initiate Labor Too Soon and Harm the Offspring

Nardhy Gomez-Lopez¹

¹Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology & Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

Abstract Text:

Preterm birth remains the leading cause of neonatal morbidity and mortality, with intra-amniotic inflammation as a key pathogenic driver. Recent research has revealed that sterile intra-amniotic inflammation (SIAI)—triggered by alarmins such as HMGB1, S100B, and IL-1α—is more prevalent than infection-driven inflammation in spontaneous preterm labor. Using a murine model with ultrasound-guided intra-amniotic alarmin injection, we demonstrated that SIAI activates the NLRP3 inflammasome, precipitating preterm birth, fetal injury, and neonatal death. Notably, Nlrp3-deficient mice were protected, underscoring the inflammasome’s central role in this process.

We also evaluated the translational potential of IL-6 pathway inhibition. Treatment with anti-IL6R monoclonal antibodies prevented preterm birth, rescued neonatal viability, and reduced inflammation-induced injury in the lungs and intestines of exposed offspring. These findings will be validated in non-human primates, emphasizing the therapeutic relevance.

In parallel, we are employing single-cell and spatial omic approaches to decipher the cellular landscape of chronic chorioamnionitis (CCA), a distinct form of in utero inflammation. Through imaging mass cytometry and single-cell RNA sequencing of human chorioamniotic membranes, we identified maternal cytotoxic effector memory T cells enriched in CCA-associated preterm births. These cells express granzyme B, proliferate locally, and contribute to emerging transcriptional signatures that may serve as predictive biomarkers.

Together, our work highlights two distinct forms of in utero inflammation—SIAI, driven by innate immune sensing of alarmins, and CCA, characterized by chronic maternal T cell infiltration—and reveals their shared capacity to initiate preterm labor and harm the developing fetus. These insights provide a mechanistic foundation for developing targeted immunomodulatory therapies to prevent inflammation-induced preterm birth and improve neonatal outcomes.