Scavengers, sensors and weavers: Cytokine and danger-signal regulation of NET clearance, trap sensing and MET formation.

Extracellular traps concentrate chromatin and bioactive proteins in the extracellular space, supporting host defence while also amplifying inflammation, thrombosis and tissue remodelling. Research has focused mainly on the formation of neutrophil extracellular traps (NETs), leaving macrophage contributions to extracellular-trap homeostasis fragmented across separate fields. Here, we organize macrophage-trap interactions into three functional roles. Macrophages act as scavengers that remove NET material, sensors that respond to trap-associated nucleic acids and damage-associated molecular patterns, and weavers that release macrophage extracellular traps (METs). These roles describe distinct functions rather than macrophage subsets or stages of a mandatory NET-to-MET sequence. Extracellular nucleases, macrophage uptake, lysosomal trafficking and TREX1-associated processing regulate the persistence of NET material. Surface, endosomal and cytosolic sensors convert NET exposure into cytokine, interferon, inflammasome and cell-fate responses. In parallel, cytokines, growth factors, calcium signalling, reactive oxygen species, peptidylarginine deiminases and membrane-trafficking pathways regulate MET deployment in stimulus- and model-dependent combinations. Tissue context places cytokines at distinct positions within these circuits, including upstream conditioning signals, outputs of NET sensing and downstream mediators acting on recipient cells. Across infection, sterile injury, fibrosis, autoimmunity and cancer, available evidence supports context-dependent protective and pathogenic effects but not a universal NET-to-MET cascade. We therefore distinguish cellular source attribution from functional causality and compare strategies that inhibit trap formation, neutralize associated cargo, degrade extracellular DNA, modulate sensing or restore clearance. Source-resolved biomarkers and mechanistically matched endpoints will be essential for translating macrophage-extracellular-trap biology without compromising protective immune functions.