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Figure 3. The mechanisms of “suicide” and “vital” NETosis. “Suicidal” NETosis can be induced by PMA or IL-8. PMA causes the release of Ca²⁺ from the ER and activation of PKC by binding to neutrophils’ surface receptors. Subsequently, the Raf-MEK-ERK signaling pathway is activated, leading to the activation of NOX and the elevation of intracellular ROS. Alternatively, IL-8 activates NF-κB by inducing the CXCR2-PI3K-AKT signaling pathway. Subsequently, iNOS and COX2 were induced to increase intracellular ROS. The increase in ROS allows NE and MPO to enter the nucleus from azurophilic granules. PAD4, on the other hand, is activated into the nucleus. NE, MPO, and PAD4 together promote chromatin decondensation. Finally, NETs are formed and released into the cell through cell membrane lysis. “Vital” NETosis can be induced by complement, microbial, and active platelet stimulation. In activated neutrophils, Ca²⁺ is transferred into the cell via SK3 channels and PAD4 is activated. Eventually, this results in the decompression of chromatin to form NETs that are transported out of the neutrophils via vesicles. Created with BioRender.com (accessed on 30 June 2022). PMA: Phorbol 12-myristate 13-acetate; IL-8: interleukin-8; ER: endoplasmic reticulum; PKC: protein kinase C; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; NOX: NADPH oxidase complex; ROS: reactive oxygen species; NF-κB: nuclear factor-kappa B; CXCR2: C-X-C chemokine receptor 2; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; iNOS: inducible nitric oxide synthase; COX2: cyclooxygenase-2; NE: neutrophil elastase; MPO: myeloperoxidase; PAD4: peptidylarginine deiminase 4; NETs: neutrophils extracellular traps; SK3: small conductance Ca²⁺ activated K⁺ channels.