Decidual lymphatic endothelial cell‐derived granulocyte‐macrophage colony‐stimulating factor induces M1 macrophage polarization via the NF‐κB pathway in severe pre‐eclampsia

Abstract

Problem Direct interactions between macrophages and lymphatic vessels have been shown previously. In pre‐eclampsia (PE), macrophages are dominantly polarized into a proinflammatory M1 phenotype and lymphangiogenesis is defective in the decidua. Here, we investigated whether decidual lymphatic endothelial cells (dLECs) affect macrophage polarization in PE. Method of Study THP‐1 macrophages were cocultured with dLECs or cultured in the conditioned medium (CM) of dLECs. Macrophage polarization was measured using flow cytometry. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) expression in dLECs was measured using qRT‐PCR and ELISA. The activation of nuclear translocation of nuclear factor‐κ (NF‐κB), an upstream signaling molecule of GM‐CSF, was assessed by immunocytochemical localization of p65. Through GM‐CSF knockdown and NF‐κB inhibition in dLEC, we evaluated whether the GM‐CSF/NF‐κB pathway of PE dLEC affects decidual macrophage polarization. Results The ratio of inflammatory M1 macrophages with HLA‐DR+/CD80+ markers significantly increased following coculturing with PE dLECs or culturing in PE dLEC CM, indicating that the PE dLEC‐derived soluble factor acts in a paracrine manner. GM‐CSF expression was significantly upregulated in PE dLECs. Recombinant human GM‐CSF induced macrophage polarization toward an M1‐like phenotype, whereas its knockdown in PE dLECs suppressed it, suggesting PE dLECs induce M1 macrophage polarization by secreting GM‐CSF. The NF‐κB p65 significantly increased in PE dLECs compared to the control, and pretreatment with an NF‐κB inhibitor significantly suppressed GM‐CSF production from PE dLECs. Conclusions In PE, dLECs expressing high levels of GM‐CSF via the NF‐κB‐dependent pathway play a role in inducing decidual M1 macrophage polarization.

Macrophage Polarizations in the Placenta and Lung are Associated with Bronchopulmonary Dysplasia

“…The intricate relationship between labor and monocyte/macrophage polarization is a fascinating yet understudied area of study within reproductive immunology. [35][36][37] Monocytes, as key components of the innate immune system, play a crucial role in the dynamic processes associated with labor, contributing to both the initiation and resolution of this complex physiological event. During labor, the uterine environment undergoes significant changes, marked by inflammation and tissue remodeling.…”