Padi4 Regulates NET Formation and Inflammatory Cell Death Downstream of Mlkl

Abstract

Abstract Neutrophil extracellular trap (NET) formation can generate short-term functional anucleate cytoplasts and can trigger loss of cell viability. We examined the role of non-apoptotic cell death signaling in NET formation by studying necroptotic human and mouse neutrophils. Necroptotic cell death signaling was activated by caspase-8 inhibition and pharmacological targeting of inhibitor of apoptosis proteins (IAPs). The specificity of cell death was confirmed using neutrophils from mice deficient in receptor-interacting protein kinase-3 (Ripk3), Ripk1 kinase activity (Ripk1D138N/D138N), caspase-8, or the plasma membrane-disrupting effector protein mixed lineage kinase doma..