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AQP3-mediated H₂O₂ transport drives macrophage M1 polarization and cervical matrix remodeling in cervical
Hanbo Liu1,2, Lingyan Chen1,2, Yuhong Long2
1Department of Obstetrics, Longgang District Maternity and Child Healthcare Hospital of Shenzhen City, Longgang Maternity and Child Institute of Shantou University Medical College, Shenzhen, Guangdong, China.
Cervical insufficiency (CI) affects 0.1%-2% of pregnancies and represents a significant cause of second-trimester pregnancy loss and preterm birth; yet, its pathophysiology remains incompletely understood. This study investigated whether aquaporin-3 (AQP3) facilitates hydrogen peroxide (H₂O₂) transport into cervical macrophages, driving their polarization toward a pro-inflammatory phenotype and subsequent cervical matrix degradation. Cervical tissues from women with CI demonstrated 1.45-fold higher AQP3 expression compared to gestational age-matched controls, with increased colocalization with macrophages. Tissue H₂O₂ levels were elevated 2.43-fold in CI, accompanied by increased oxidative damage markers and reduced collagen content. In vitro studies using THP-1 macrophages revealed that AQP3 knockdown prevented intracellular H₂O₂ accumulation despite pro-inflammatory stimulation, blocking M1 polarization and NF-κB activation. Co-culture experiments demonstrated that AQP3-dependent M1 macrophages increased matrix metalloproteinase (MMP)-9 activity 3.8-fold and reduced fibroblast collagen content by 59%. Both H₂O₂ scavenging with PEG-catalase and NF-κB inhibition with Bay 11-7082 prevented macrophage-mediated matrix degradation. These findings suggest that AQP3 may serve as an important mediator linking oxidative stress to inflammatory cervical remodeling through facilitation of H₂O₂ influx, NF-κB activation, and M1 macrophage polarization. Targeting AQP3 or its downstream signaling may represent a potential therapeutic approach that requires preclinical validation to prevent CI-associated pregnancy complications.
Cervical insufficiency (CI) affects 0.1%-2% of pregnancies and represents a significant cause of second-trimester pregnancy loss and preterm birth; yet, its pathophysiology remains incompletely understood. This study investigated whether aquaporin-3 (AQP3) facilitates hydrogen peroxide (H₂O₂) transport into cervical macrophages, driving their polarization toward a pro-inflammatory phenotype and subsequent cervical matrix degradation. Cervical tissues from women with CI demonstrated 1.45-fold higher AQP3 expression compared to gestational age-matched controls, with increased colocalization with macrophages. Tissue H₂O₂ levels were elevated 2.43-fold in CI, accompanied by increased oxidative damage markers and reduced collagen content. In vitro studies using THP-1 macrophages revealed that AQP3 knockdown prevented intracellular H₂O₂ accumulation despite pro-inflammatory stimulation, blocking M1 polarization and NF-κB activation. Co-culture experiments demonstrated that AQP3-dependent M1 macrophages increased matrix metalloproteinase (MMP)-9 activity 3.8-fold and reduced fibroblast collagen content by 59%. Both H₂O₂ scavenging with PEG-catalase and NF-κB inhibition with Bay 11-7082 prevented macrophage-mediated matrix degradation. These findings suggest that AQP3 may serve as an important mediator linking oxidative stress to inflammatory cervical remodeling through facilitation of H₂O₂ influx, NF-κB activation, and M1 macrophage polarization. Targeting AQP3 or its downstream signaling may represent a potential therapeutic approach that requires preclinical validation to prevent CI-associated pregnancy complications.
