Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Abstract

Pre‐eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger‐sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod‐like receptor protein (NLRP)3 inflammasome to release interleukin (IL)‐1β and result in vigorous inflammation. We aimed to characterize crystal‐induced NLRP3 activation in placental inflammation and examine its role in pre‐eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre‐eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C‐reactive protein (hsCRP) and the pre‐eclampsia marker soluble fms‐like tyrosine kinase‐1 (sFlt‐1). The NLRP3 inflammasome pathway components (NLRP3, caspase‐1, IL‐1β) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co‐expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL‐1β and TCC was increased significantly and C5a‐positive regions in the syncytiotrophoblast layer appeared more frequent in pre‐eclamptic compared to normal pregnancies. In‐vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement‐primed crystal‐induced release of IL‐1β. This study confirms crystal‐induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre‐eclampsia.