Cytokine signalling in formation of neutrophil extracellular traps: Implications for health and diseases

Neutrophils, as essential component of the innate immune response, form a crucial part in the defence mechanisms through the release of extracellular traps (NETs). These web-like structures, composed of chromatin and antimicrobial proteins, are essential for the entrapment and inactivation of pathogens. However, either constitutive formation or inefficient clearance of NETs leads to adverse effects such as fibrosis, thrombosis, delayed wound healing and tissue damage in multiple diseases associated with sterile inflammation. This dichotomy casts NETs as both protective agents and harmful factors in several diseases such as autoimmune diseases, metabolic syndromes, systemic infections, and malignancies. Besides microbes and their products, variety of stimulants including pro-inflammatory cytokines induce NETs. The complex interactions and cross talk among the pro-inflammatory cytokines including IL-8, IL-6, GM-CSF, TNF-α, IFNs, and IL-1β activate neutrophils to form NETs and also contributes to a vicious circle of inflammatory cascade, leading to increased inflammation, oxidative stress, and thrombotic events. Emerging evidence indicates that the dysregulated cytokine milieus in diseases, such as diabetes mellitus, obesity, atherosclerosis, stroke, rheumatoid arthritis, and systemic lupus erythematosus, potentiate NETs release, thereby promoting disease development. Thus, neutrophils represent both critical effectors and a potential target of therapy in these strategies, underscoring their importance in the context of cytokine-mediated therapies for a spectrum of diseases. In the present review, we describe various cytokines and associated signalling pathways activating NETs formation in different human pathologies. Further, the review identifies potential strategies to pharmacologically modulate cytokine pathways to reduce NETs. • Diseases associated with sterile inflammation show elevated NETs • Pro-inflammatory cytokines induce robust formation of NETs • Bidirectional activation of cytokines and oxidative stress facilitate NETs activation • Cytokine activated NETs perpetuate inflammation, thrombosis and tissue injury • Cytokine signalling may serve as potential therapeutic target to reduce NETs burden