Complement Modulation Mitigates Inflammation-Mediated Preterm Birth and Fetal Neural Inflammation

Preterm birth and the neonatal pathological sequelae that follow spontaneous preterm labor are closely associated with maternal and fetal inflammatory activation. Previous studies have indicated a role for the complement system in this inflammatory response. Utilizing an LPS inflammation-induced model of preterm birth, we investigated various delivery outcomes and their correlation with complement activation products within cervical, uterine, and fetal brain tissue after administration of LPS. We provide further evidence that complement-mediated inflammation within cervical and uterine tissue contributes to aberrant cellular changes and an increase in preterm delivery. We additionally show that a targeted complement inhibitor that specifically targets to sites of complement activation (CR2-Crry) mitigates the effects of LPS-induced pathology and preterm birth. Complement inhibition increased latency to delivery, mean gestational age at delivery, and average number of viable pups. Furthermore, the improved delivery outcomes seen with CR2-Crry treatment correlated with a reduced inflammatory response in maternal tissue and in fetal brain tissue in terms of reduced complement activation, reduced pro-inflammatory cytokines, and reduced macrophage recruitment. These data indicate that complement inhibition represents a potential therapeutic strategy for preventing preterm birth. The localization of complement inhibition by a site-targeting approach reduces the possibility of unwanted off-target effects.