PAD4 deficiency decreases inflammation and susceptibility to pregnancy loss in a mouse model

Inflammation is thought to play a critical role in the pathogenesis of placentation disorders such as recurrent miscarriages, growth restriction, and preeclampsia. Recently, neutrophil extracellular traps (NETs) have emerged as a potential mechanism for promoting inflammation in both infectious and noninfectious disorders. To investigate a pathogenic role for NETs in placentation disorders, we studied a model of antiangiogenic factor-mediated pregnancy loss in wildtype (WT) mice and in mice deficient in peptidylarginine deiminase 4 (Padi4^-/-) that are unable to form NETs. Overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein that is pathogenically linked with abnormal placentation disorders during early gestation, resulted in pregnancy loss and large accumulation of neutrophils and NETs in WT placentas. Interestingly, sFlt-1 overexpression in Padi4^-/- mice resulted in dramatically lower inflammatory and thrombotic response, which was accompanied by significant reduction in pregnancy losses. Inhibition of NETosis may serve as a novel target in disorders of impaired placentation.