PZP deficiency impairs M2 macrophage polarization via TGF-β/Smad3 signaling, contributing to immune dysregulation at the maternal-fetal interface in preeclampsia.

BACKGROUND

Preeclampsia (PE) is characterized by immune dysregulation at the maternal-fetal interface, particularly an imbalance in macrophage polarization (elevated M1/M2 ratio). Pregnancy zone protein (PZP), a placenta-derived immunomodulator, is dysregulated in PE, but its functional role and mechanism remain unclear.

OBJECTIVE

To investigate the role and mechanism of trophoblast-derived PZP in regulating macrophage polarization and its contribution to PE pathogenesis.

METHODS

Clinical samples from PE and control pregnancies were analyzed for PZP expression, macrophage subsets, TGF-β/Smad3 pathway activity, and inflammatory markers. In vitro, PZP was knocked down or overexpressed in HTR8/SVneo trophoblasts co-cultured with THP-1-derived macrophages; polarization, cytokines, and TGF-β pathway dependence were assessed. In vivo, placenta-specific Pzp knockdown was induced in pregnant mice via AAV9-shPzp, and PE-like phenotypes, macrophage polarization, inflammation, and TGF-β signaling were evaluated, with rescue by TGF-β1.

RESULTS

PZP expression was significantly reduced in PE placentas, correlating negatively with disease severity and the M1/M2 ratio, and positively with pro-inflammatory cytokines. PZP localized to trophoblasts adjacent to macrophages. In vitro, PZP-deficient trophoblast conditioned media promoted M1 polarization (↑CD86, ↑IL-6/TNF-α, ↓CD206, ↓IL-10) and suppressed TGF-β/Smad3 signaling; these effects were significantly counteracted by PZP overexpression or exogenous TGF-β1 and blocked by TGF-β pathway inhibition. In vivo, placenta-specific Pzp knockdown induced hypertension, proteinuria, elevated placental M1/M2 ratio, and inflammation, associated with suppressed TGF-β/Smad3 signaling. TGF-β1 supplementation significantly ameliorated these phenotypes.

CONCLUSION

Trophoblast-derived PZP deficiency contributes to immune dysregulation in PE by impairing TGF-β/Smad3 signaling, which disrupts M2 macrophage polarization and promotes a pro-inflammatory state at the maternal-fetal interface. PZP represents a promising therapeutic target and a potential placental tissue marker for PE, warranting further investigation into its utility for early risk stratification.