Upregulation of Siglec-6 induces mitochondrial dysfunction by promoting GPR20 expression in early-onset preeclampsia
Preeclampsia (PE) is a pregnancy complication that seriously threatens maternal and fetal health, but its pathogenesis is unclear. A growing number of studies have revealed significant changes in the mitochondria of placental trophoblasts in PE, with abnormalities in mitochondrial content, morphology, and function, but the regulatory mechanisms are not clear. Siglec-6 belongs to the family of sialic acid-binding immunoglobulin-like lectins (Siglecs), and studies have demonstrated that the Siglecs family is capable of modulating the oxidative phosphorylation and energy metabolism of mitochondria. Our study revealed that Siglec-6, which is mainly localized in syncytiotrophoblasts (STB) and extravillous trophoblast (EVT), is abnormally up-regulated in EVT in early-onset PE (EO-PE). Siglec-6 inhibited trophoblast migration, invasion, and impaired mitochondrial function. Mechanistic studies revealed that Siglec-6 inhibits NF-?B activation by recruiting SHP1/SHP2, leading to an increase in GPR20 expression, which further suppresses the downstream c-AMP/PKA/ERK signaling pathway and causes mitochondrial dysfunction in trophoblast cells. Placenta-specific overexpression of Siglec-6 in an animal model causes impaired placental structure and vessel formation, leading to a PE-like phenotype in mice. We conclude that trophoblast upregulated Siglec-6 induced trophoblast mitochondrial dysfunction through the SHP1/SHP2-NF-?B-GPR20 signaling pathway, leading to diminished trophoblast migration, invasion, and ultimately mediating the development of PE. Our study provides new ideas for the pathogenesis of PE and may provide new targets for the prevention or treatment of PE. Overall design: Comparative gene expressing profiling analysis of RNA-seq data for HTR8/SVneo cells overexpressing Siglec-6 and nagative control.