Chromatin Decompaction-Induced Intranuclear Pressure Drives Nuclear Envelope Rupture During NETosis

Neutrophils can kill pathogens or damage the host by releasing decompacted chromatin as neutrophil extracellular traps (NETs) during NETosis. A key step in NETosis is the rupture of the nuclear envelope (NE), proposed to be mediated by biochemical modifications of the nuclear lamina. Here, using biophysical approaches, we show that the physical properties of the nucleus drastically change leading to NE rupture during NETosis. High-resolution live microscopy revealed that the lamina remains intact and recoils during NE rupture suggesting that intranuclear forces drive NE rupture. Fluorescence recovery after photobleaching and atomic force microscopy measurements showed that as chromatin decompacts, the mobility of histones, intranuclear pressure, and nuclear surface tension increase prior to NE rupture. We hypothesized that chromatin decompaction increases nuclear osmotic pressure driving NE rupture. Consistently, we showed that hypo/hyper osmotic shocks promote/prevent NE rupture. Beyond NETosis, our work reveals that changes in chromatin compaction state can dynamically regulate the mechanical properties of the nucleus and downstream cell functions.