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)-1ß 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-1ß) 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-1ß 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-1ß. 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.
Subject(s)
Alarmins/metabolism , Cholesterol/blood , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Placenta/pathology , Pre-Eclampsia/pathology , Uric Acid/blood , C-Reactive Protein/metabolism , Caspase 1/metabolism , Cholesterol/metabolism , Complement C5a/immunology , Complement Membrane Attack Complex/metabolism , Female , Humans , Inflammasomes/immunology , Inflammation/pathology , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Placenta/immunology , Pre-Eclampsia/blood , Pre-Eclampsia/immunology , Pregnancy , Trophoblasts/metabolism , Uric Acid/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolismABSTRACT
By application of a monoclonal antibody (Abbott ER-ICA) oestrogen receptors can now be demonstrated and semiquantitated on paraffin sections after fixation in formalin. In a prospective series of 22 breast carcinomas we found that 82% (18/22) were oestrogen receptor positive. The frequency was significantly lower in archival tissue comprising 27 invasive carcinomas (56%) and in 63 intraductal carcinomas (54%). Even lower frequencies were found in recurrences and metastases and none (0/10) of the metastases from tumours of unknown origin were oestrogen receptor positive. It is likely that prolonged fixation in formalin destroys the receptor protein. Immunocytochemical assessment of oestrogen receptor may be the only alternative when dealing with small breast tumours (< 1 cm), in cases of suspected recurrences and in cases of unknown receptor status.
