Upregulation of PLAAT3 in syncytiotrophoblast induces activation of neutrophils via LPA-LPAR5 axis in preeclampsia

Background: Preeclampsia is a life-threatening disease of pregnancy that features abnormal placental changes and immune activation. Although lipid metabolic dysfunction in the placenta and maternal circulation is commonly observed in preeclampsia, its mechanistic role in disease pathogenesis remains unclear.

Methods: Transcriptome RNA Sequencing was performed on placentas of early-onset preeclampsia (EOPE) patients and control pregnant women. RT-qPCR, Western blot and immunostaining were conducted to determine the expression and location of PLAAT3. Neutrophils in placenta were detected by immunostaining of CD15, CD66b, myeloperoxidase and neutrophil Elastase. Syncytial-BeWo cells transfected with PLAAT3-overexpressed or control plasmids were collected for RNA Sequencing. The effects of PLAAT3 overexpressed-syncytiotrophoblast (STB) and lipid metabolite lysophosphatidic acid (LPA) on neutrophils were investigated using RT-qPCR, Luminex, Transwell and Adhesion assays. The levels of LPA in placenta and culture supernatant of syncytial-BeWo cells were detected by ELISA.

Results: In placentas from patients with EOPE, dysregulation of lipid metabolism pathways was observed, marked by a pronounced upregulation of PLAAT3 in STB. This dysregulation coincided with prominent neutrophil infiltration and activation within placental tissues. PLAAT3-overexpressed STB increased the chemotactic migration and adhesion of neutrophils, and enhanced inflammatory cytokines production and neutrophil extracellular traps formation. Notably, our analysis revealed significantly elevated LPA levels in placental tissue from EOPE patients and in culture media from PLAAT3-overexpressed STB. Furthermore, mechanistic investigations demonstrated that PLAAT3-mediated neutrophil regulation is dependent on the LPA/LPAR5 signaling axis.

Discussion: Our findings demonstrate that PLAAT3 might participate in the pathogenesis of EOPE by promoting the activation of neutrophils via LPA-LPAR5 axis.

LPA; Neutrophil; PLAAT3; Placenta; Preeclampsia.