Magnesium ammonium phosphate hexahydrate (struvite) crystals induce macrophage extracellular traps, migrasomes and...

Current research on magnesium ammonium phosphate hexahydrate (MAP) stones has focused exclusively on MAP crystal formation, while the mechanisms by which MAP crystals damage macrophages and contribute to stone formation remain unreported. Given the prevalence of urinary tract inflammation and cellular injury in MAP stone patients, and the pivotal role of macrophages in inflammation, this study investigated the interaction between MAP crystals and macrophages, as well as their potential effects on MAP stone formation. MAP crystals (≈4 μm) were synthesized, characterized, and their interaction with macrophages, cytotoxicity, and expression of key proteins in the caspase-1-mediated pyroptosis pathway were detected. Results showed MAP crystals had significant cytotoxicity. Besides canonical endocytosis and adhesion, they induced macrophage extracellular traps (METs), a newly identified interaction between MAP crystals and macrophages. MAP crystals also triggered massive migrasome production to exacerbate local inflammation (not observed in MAP-saturated solution) and induced more pronounced macrophage pyroptosis than MAP solution. In conclusion, MAP crystals induce METs formation, migrasome production, and pyroptosis in macrophages, impairing the macrophage biomembrane system and exacerbating inflammation, thereby increasing stone formation risk, providing a scientific basis for elucidating MAP stone formation mechanisms.