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. 2024 May 1;56(5):1055–1065. doi: 10.1038/s12276-024-01219-w

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024

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Fig. 2 — Various stimuli, including microbes, cytokines, PMA, platelets, monosodium urate (MSU) crystals, and nitric oxidase, can induce the formation of NETs. During this process, neutrophils undergo morphological changes to become rounded and have uniformly condensed chromatin. Neutrophils are activated to produce cytosolic ROS through the NOX2 complex. This activation prompts the release of neutrophil elastase (NE) and myeloperoxidase (MPO) from granules, followed by nuclear translocation of NE and MPO and the induction of chromatin decondensation. Subsequently, the nuclear envelope breaks down, leading to the fusion of DNA-containing vesicles with the plasma membrane. This cascade ultimately results in the formation of nuclear NETs. Additionally, elevated intracellular calcium levels induced by calcium ionophores can activate PAD4 independently of the NOX2 complex. PAD4 is translocated to the nucleus to drive histone citrullination/carbamylation and chromatin decondensation through a NOX2-independent mechanism.