Neutrophil extracellular trap formation pathway (NETosis) (NETosis)

The Neutrophil Extracellular Trap (NET) formation pathway, or NETosis, is a specialized innate immune response where neutrophils release web-like scaffolds of chromatin decorated with antimicrobial proteins to capture and neutralize pathogens (Jorch & Kubes, 2017). While essential for host defense, dysregulated or excessive NETosis is a major driver of tissue damage and chronic inflammation in conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and COVID-19-related coagulopathy (Papayannopoulos, 2018). Furthermore, NETs are known to promote thrombosis by providing a scaffold for platelet aggregation and to facilitate cancer metastasis by sequestering circulating tumor cells (Demers & Wagner, 2014). Pharmacological intervention focuses on inhibiting key regulatory enzymes like Peptidylarginine deiminase 4 (PAD4), which is essential for chromatin decondensation, or using DNases to enzymatically digest the DNA scaffold (Wang et al., 2009). Balancing the inhibition of this pathway is critical, as complete suppression may predispose patients to severe bacterial and fungal infections.

Other names

NETosisNET formationNeutrophil extracellular traps

Inhibition of Peptidylarginine deiminase 4 (PAD4) to prevent histone citrullination and chromatin decondensation; degradation of extracellular DNA scaffolds using DNases; inhibition of Neutrophil elastase (NE) to prevent nuclear envelope breakdown; and inhibition of Gasdermin D (GSDMD) to prevent plasma membrane pore formation and NET release.