Placenta-derived IL-32\u03b2 activates neutrophils to promote preeclampsia development

Dan Liu,Zhiyin Wang,Xiangyu Zhu,Guangfeng Zhao,Qianwen Wu,Ya Wang,Yayi Hou,Qiang Li,Honglei Duan,Chenrui Cao,Yali Hu,Hailin Ding,Mingming Zheng,Huirong Tang,Xianyan Lu,Yimin Dai

doi:10.1038/s41423-021-00636-5

Dan Liu, Zhiyin Wang + Show 14 more

Open Access

https://doi.org/10.1038/s41423-021-00636-5

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Abstract

Immune activation at the maternal-fetal interface is a main pathogenic factor of preeclampsia (PE). Neutrophils (PMNs) are activated in PE patients, but the mechanism and consequences of PMN activation need to be further explored. Here, we demonstrated that interleukin-32 (IL-32) expression was significantly upregulated in syncytiotrophoblasts (STBs) and that IL-32β was the major isoform with increased expression in the placenta of severe PE (sPE) patients. Furthermore, the level of IL-32 expression in the placenta was correlated with its level in the serum of sPE patients, indicating that IL-32 in the serum is derived mainly from the placenta. Then, in vitro experiments showed that IL-32β could highly activate PMNs and that these IL-32β-activated PMNs were better able to adhere to endothelial cells (HUVECs) and enhance the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) in HUVECs, which could be reversed by preincubation with the NADPH oxidase inhibitor VAS 2870. In addition, we showed that IL-32β mainly activated PMNs by binding to proteinase 3. Finally, IL-32β administration induced a PE-like phenotype in a pregnant mouse model. This study provides evidence of the involvement of IL-32β in the pathogenesis of PE.

Highlights

IntroductionPreeclampsia (PE) is a serious complication in pregnancy that threatens the health and even the life of the mother and fetus[1]
Preeclampsia (PE) is a serious complication in pregnancy that threatens the health and even the life of the mother and fetus[1]. the mechanisms underlying PE remain elusive, disturbance of maternal immune tolerance to the semiallogeneic fetus is recognized as one of the key pathologies of PE2–5
The level of IL-32 in the placenta is upregulated and correlated with the serum level in severe PE (sPE) patients To study the role of IL-32 in PE, we evaluated IL-32 expression in human placenta tissue from patients with sPE (n = 22) and noninfected preterm birth (nPTB) (n = 12) (Fig. 1)

Summary

Introduction

Preeclampsia (PE) is a serious complication in pregnancy that threatens the health and even the life of the mother and fetus[1]. The mechanisms underlying PE remain elusive, disturbance of maternal immune tolerance to the semiallogeneic fetus is recognized as one of the key pathologies of PE2–5. PMNs in PE pregnancy produce a large number of reactive oxygen species (ROS)[9,10] and express high levels of the adhesion molecules CD11b and intercellular cell adhesion molecule-1 (ICAM-1)[11,12,13], which may increase the number of PMNs adhered to the endothelium and infiltrated in the intimal space of the maternal systemic vasculature[11,12]. Some studies have shown that the placental villus culture supernatant[14] and plasma[15] of PE patients stimulate activation of maternal

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