PAD4 |
Mediates histone citrullination, be involved in NF-κB activation and IL-1β release, PAD4 inhibitors reduce the formation of NETs, and PAD4 enzymes promote the production of NETs. |
[35,36,79,80,82] |
ROS |
Participates in classic NETosis, and triggers the separation, release, and migration of NE and MPO to the neutrophil nucleus. |
[9,77,84] |
Platelets |
Activate neutrophils via TLR4 to release NETs. |
[29,31] |
Signaling pathways |
Raf-MEK-ERK pathway |
Activates NADPH oxidase and upregulates anti-apoptotic proteins, promoting the formation of NETs. |
[30] |
Lipoxin pathway |
Regulates the calcium flux of neutrophils, participates in citrullination and ROS production, and regulates neutrophil apoptosis and promotes NET formation. |
[20] |
NF-κB/CXCR1 pathway |
Activation promotes the formation of NETs. |
[85] |
Cytokines and others |
IL-8 |
Triggers the cleavage of gasdermin D by serine proteases, leading to pore formation and NET formation, the content was correlated with the concentration of NETs in BALF. |
[82,91] |
Gasdermin D (GSDMD) |
Forms pores in the granular and plasma membranes, allowing NE to enter the cytoplasm and NETs to be released outside the neutrophils. |
[90] |
IL17A |
Induces NET production through STAT3 activation with other cofactors. |
[92] |
Integrins and G-protein coupled receptors |
Necessary for NET formation during the VILI process. |
[31] |
CCL5/CXCL4 heterodimers |
Blocking inhibits the formation of NETs. |
[31] |
Complement |
Inhibition of activation reduces the release of NETs. |
[93] |
miR144, miR155 |
Promotes NET formation. |
[81,85] |
PD-L1 |
Inhibits autophagy of neutrophils and maintain the release of NETs through the PI3K/Akt/mTOR pathway. |
[94] |
Interferon inducer poly I:C |
Induces the formation of NETs via activation of P38 MAPK and decreased expression of the tight-linking protein claudin-5. |
[95] |